β-Lactamyl vasopressin V1a Antagonists

ABSTRACT

Novel 2-(azetidin-2-on-1-yl)alkanedioic acid derivatives and 2-(azetidin-2-on-1-yl)alkoxyalkanoic acid derivatives are described for use in the treatment of disease states responsive to antagonism of the vasopressin V 1a  receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national counterpart application filed under35 U.S.C. § 371 of International Application Serial No.PCT/US2002/032433 filed Oct. 11, 2002, which claims priority toProvisional Patent Application Ser. No. 60/329,054 filed Oct. 12, 2001.

This invention was made with support from NIH Grant Nos. R41 HD37290 andR42 HD37290; the government may have certain fights in this invention.

FIELD OF THE INVENTION

The present invention relates to novel 2-(azetidin-2-on-1-yl)alkanedioicacid derivatives as vasopressin V_(1a) receptor antagonists. The presentinvention also relates to methods of treating mammals in need of relieffrom disease states associated with and responsive to the antagonism ofthe vasopressin V_(1a) receptor.

BACKGROUND OF THE INVENTION

Vasopressin, a neurohypophyseal neuropeptide produced in thehypothalamus, is involved in water metabolism homeostasis, renalfunction, mediation of cardiovascular function, non-opioid mediation oftolerance for pain, and regulation of temperature in mammals. Inaddition to being released into the circulation via the posteriorpituitary, vasopressin acts as a neurotransmitter in the brain. Threevasopressin receptor subtypes, designated V_(1a), V_(1b), and V₂ havebeen identified. The human V_(1a) receptor has been cloned (Thibonnieret al., The Journal of Biological Chemistry, 269(5), 3304–3310 (1994)),and has been shown by radioligand binding techniques to be present invascular smooth muscle cells, hepatocytes, blood platelets, lymphocytesand monocytes, type II pneumocytes, adrenal cortex, brain, reproductiveorgans, retinal epithelium, renal mesangial cells, and the A10, A7r5,3T3 and WRK-1 cell lines (Thibonnier, Neuroendocrinology of the Conceptsin Neurosurgery Series 5, (Selman, W., ed), 19–30, Williams and Wilkins,Baltimore, (1993)).

Structural modification of vasopressin has provided a number ofvasopressin agonists (Sawyer, Pharmacol. Reviews, 13, 255 (1961)). Inaddition, several potent and selective vasopressin peptide antagonistshave been designed (Lazslo et al., Pharmacological Reviews, 43, 73–108(1991); Mah and Hofbauer, Drugs of the Future, 12, 1055–1070 (1987);Manning and Sawyer, Trends in Neuroscience, 7, 8–9 (1984)). Their lackof oral bioavailability and short half-life, however, have limited thetherapeutic potential of these analogs. While novel structural classesof non-peptidyl vasopressin V_(1a) antagonists have been discovered(Yamamura et al., Science, 275, 572–574 (1991); Serradiel-Le Gal et al.,Journal of Clinical Investigation, 92, 224–231 (1993); Serradiel-Le Galet al., Biochemical Pharmacology, 47(4), 633–641 (1994)), a clinicalcandidate has yet to be identified.

The general structural class of substituted 2-(azetidin-2-on-1-yl)aceticacid esters and amides are known as synthetic intermediates for thepreparation of β-lactam antibiotics (see e.g. U.S. Pat. No. 4,751,299).

SUMMARY OF THE INVENTION

It has been found that certain compounds within the general class of2-(azetidin-2-on-1-yl)alkanedioic acid derivatives elicit activity atthe vasopressin V_(1a) receptor. The present invention describes novel2-(azetidin-2-on-1-yl)alkanedioic acid esters and amides useful fortreating disease states that are associated with and responsive toantagonism of a vasopressin V_(1a) receptor in a mammal.

The invention also describes a method for treating a disease stateresponsive to the antagonism of a vasopressin V_(1a) receptor, in amammal in need of such treatment, comprising the step of administeringto the mammal a pharmaceutically effective amount of such2-(azetidin-2-on-1-yl)alkanedioic acid derivatives.

In particular, the present invention describes compounds having theformula I:

wherein:

n is an integer from 0 to 2;

A is R⁶O—, monosubstituted amino, or disubstituted amino;

A′ is R^(6′)O—, monosubstituted amino, or disubstituted amino;

R² is hydrogen or C₁–C₆ alkyl;

R³ is a structure selected from the group consisting of

R⁴ is C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl, C₃–C₉cycloalkenyl, limonenyl, pinenyl, C₁–C₃ alkanoyl, optionally-substitutedaryl, optionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(C₂–C₄ alkenyl), or optionally-substituted aryl(C₂–C₄ alkynyl);

R⁶ and R^(6′) are each independently selected from the group consistingof C₁–C₆ alkyl, C₃–C₈ cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄ alkyl),optionally-substituted aryl(C₁–C₄ alkyl), a first heterocycle Y—,Y—(C₁–C₄ alkyl), a second heterocycle Y′—, Y′—(C₁–C₄ alkyl),R⁷R⁸N—(C₂–C₄ alkyl), and R^(7′)R^(8′)N—(C₂–C₄ alkyl);

-   -   where the first heterocycle Y and the second heterocycle Y′ are        each independently selected from the group consisting of        tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl,        piperazinyl, homopiperazinyl, or quinuclidinyl; where said        morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl,        homopiperazinyl, or quinuclidinyl is optionally N-substituted        with C₁–C₄ alkyl or optionally-substituted aryl(C₁–C₄ alkyl);

R⁷ is hydrogen or C₁–C₆ alkyl;

R⁸ is C₁–C₆ alkyl, C₃–C₈ cycloalkyl, optionally-substituted aryl, oroptionally-substituted aryl(C₁–C₄ alkyl); or

-   -   R⁷ and R⁸ are taken together with the attached nitrogen atom to        form an heterocycle selected from the group consisting of        pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and        homopiperazinyl; where said piperazinyl or homopiperazinyl is        optionally N-substitued with R¹²;

R⁷′ is hydrogen or C₁–C₆ alkyl;

R⁸′ is C₁–C₆ alkyl, C₃–C₈ cycloalkyl, optionally-substituted aryl, oroptionally-substituted aryl(C₁–C₄ alkyl); or

-   -   R^(7′) and R^(8′) are taken together with the attached nitrogen        atom to form an heterocycle selected from the group consisting        of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and        homopiperazinyl; where said piperazinyl or homopiperazinyl is        optionally N-substituted with R^(12′);

R¹⁰ and R¹¹ are each independently chosen from the group consisting ofhydrogen, C₁–C₆ alkyl, C₃–C₅ cycloalkyl, C₁–C₄ alkoxycarbonyl, C₁–C₅alkanoyloxy, benzyloxy, benzoyloxy, diphenylmethoxy, triphenylmethoxy,optionally-substituted aryl, and optionally-substituted aryl(C₁–C₄alkyl);

-   -   where the C₁–C₆ alkyl or the C₃–C₈ cycloalkyl is optionally        monosubstituted with a substituent selected from the group        consisting of hydroxy, protected carboxy, carbamoyl, thiobenzyl        and C₁–C₄ thioalkyl; and,    -   where the benzyl of said benzyloxy or said benzoyloxy is        optionally substituted with one or two substituents        independently selected from the group consisting of C₁–C₄ alkyl,        C₁–C₄ alkoxy, halogen, hydroxy, cyano, carbamoyl, amino,        mono(C₁–C₄ alkyl)amino, di(C₁–C₄ alkyl)amino, C₁–C₄        alkylsulfonylamino, and nitro;

R¹² and R^(12′) are each independently selected from the groupconsisting of hydrogen, C₁–C₆ alkyl, C₃–C₈ cycloalkyl, C₁–C₄alkoxycarbonyl, optionally-substituted aryloxycarbonyl,optionally-substituted aryl(C₁–C₄ alkyl), and optionally-substitutedaryloyl; and

hydrates, solvates and pharmaceutically acceptable acid addition saltsthereof; and

providing that:

a) when A is R⁶O—, then A′ is not benzylamino or substitutedbenzylamino;

b) when A is R⁶O— and the integer n is 0, then A′ is not R^(6′)O—; and

c) when A is monosubstituted amino and the integer n is 0, then A′ isnot anilinyl, substituted anilinyl, benzylamino, or substitutedbenzylamino.

In addition, the present invention describes compounds having theformula II:

wherein:

n′ is an integer from 1 to 3;

A is R⁶O—, monosubstituted amino, or disubstituted amino;

R² is hydrogen or C₁–C₆ alkyl;

R³ is a structure selected from the group consisting of

R⁴ is C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl, C₃–C₉cycloalkenyl, limonenyl, pinenyl, C₁–C₃ alkanoyl, optionally-substitutedaryl, optionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(halo C₁–C₄ alkyl), optionally-substituted aryl(alkoxy C₁–C₄ alkyl),optionally-substituted aryl(C₂–C₄ alkenyl), optionally-substitutedaryl(halo C₂–C₄ alkenyl), or optionally-substituted aryl(C₂–C₄ alkynyl);

R⁶ is selected from the group consisting of C₁–C₆ alkyl, C₃–C₈cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄ alkyl), optionally-substitutedaryl(C₁–C₄ alkyl), a first heterocycle Y—, Y—(C₁–C₄ alkyl), andR⁷R⁸N—(C₂–C₄ alkyl);

-   -   where the first heterocycle Y is selected from the group        consisting of tetrahydrofuryl, morpholinyl, pyrrolidinyl,        piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl;        where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl,        homopiperazinyl, or quinuclidinyl is optionally N-substituted        with C₁–C₄ alkyl or optionally-substituted aryl(C₁–C₄ alkyl);

R^(6′) is selected from the group consisting of C₁–C₆ alkyl, C₃–C₈cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄ alkyl), optionally-substitutedaryl(C₁–C₄ alkyl), Y′—(C₁–C₄ alkyl), where Y′— is a second heterocycle,and R^(7′)R^(8′)N—(C₂–C₄ alkyl);

-   -   where the second heterocycle Y′ is selected from the group        consisting of tetrahydrofuryl, morpholinyl, pyrrolidinyl,        piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl;        where said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl,        homopiperazinyl, or quinuclidinyl is optionally N-substituted        with C₁–C₄ alkyl or optionally-substituted aryl(C₁–C₄ alkyl);

R⁷ is hydrogen or C₁–C₆ alkyl;

R⁸ is C₁–C₆ alkyl, C₃–C₈ cycloalkyl, optionally-substituted aryl, oroptionally-substituted aryl(C₁–C₄ alkyl); or

-   -   R⁷ and R⁸ are taken together with the attached nitrogen atom to        form an heterocycle selected from the group consisting of        pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and        homopiperazinyl; where said piperazinyl or homopiperazinyl is        optionally N-substitued with R¹²;

R^(7′) is hydrogen or C₁–C₆ alkyl;

R^(8′) is C₁–C₆ alkyl, C₃–C₈ cycloalkyl, optionally-substituted aryl, oroptionally-substituted aryl(C₁–C₄ alkyl); or

-   -   R^(7′) and R^(8′) are taken together with the attached nitrogen        atom to form an heterocycle selected from the group consisting        of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and        homopiperazinyl; where said piperazinyl or homopiperazinyl is        optionally N-substituted with R^(12′);

R¹⁰ and R¹¹ are each independently chosen from the group consisting ofhydrogen, C₁–C₆ alkyl, C₃–C₈ cycloalkyl, C₁–C₄ alkoxycarbonyl, C₁–C₅alkanoyloxy, benzyloxy, benzoyloxy, diphenylmethoxy, triphenylmethoxy,optionally-substituted aryl, and optionally-substituted aryl(C₁–C₄alkyl);

-   -   where the C₁–C₆ alkyl or the C₃–C₈ cycloalkyl is optionally        monosubstituted with a substituent selected from the group        consisting of hydroxy, protected carboxy, carbamoyl, thiobenzyl        and C₁–C₄ thioalkyl; and,    -   where the benzyl of said benzyloxy or said benzoyloxy is        optionally substituted with one or two substituents        independently selected from the group consisting of C₁–C₄ alkyl,        C₁–C₄ alkoxy, halogen, hydroxy, cyano, carbamoyl, amino,        mono(C₁–C₄ alkyl)amino, di(C₁–C₄ alkyl)amino, C₁–C₄        alkylsulfonylamino, and nitro;

R¹² and R^(12′) are each independently selected from the groupconsisting of hydrogen, C₁–C₆ alkyl, C₃–C₈ cycloalkyl, C₁–C₄alkoxycarbonyl, optionally-substituted aryloxycarbonyl,optionally-substituted aryl(C₁–C₄ alkyl), and optionally-substitutedaryloyl; and

hydrates, solvates and pharmaceutically acceptable acid addition saltsthereof.

Illustrative compounds of formula I and II are described, wherein A isan acyclic disubstituted amino.

Illustrative compounds of formula I and II are described 1, wherein A isa cyclic disubstituted amino.

Illustrative compounds of formula I and II are described, wherein A is amonosubstituted amino having the formula XNH—, where X is selected fromthe group consisting of C₁–C₆ alkyl, C₃–C₈ cycloalkyl, (C₁–C₄alkoxy)-(C₁–C₄ alkyl), optionally-substituted aryl,optionally-substituted aryl(C₁–C₄ alkyl), the first heterocycle Y,Y—(C₁–C₄ alkyl), R⁷R⁸N—, and R⁷R⁸N—(C₂–C₄ alkyl).

Illustrative compounds of formula I and II are described, wherein A is adisubstituted amino having the formula R⁵XN—; where R⁵ is selected fromthe group consisting of hydroxy, C₁–C₆ alkyl, C₁–C₄ alkoxycarbonyl, andbenzyl; and where X is selected from the group consisting of C₁–C₆alkyl, C₃–C₈ cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄ alkyl),optionally-substituted aryl, optionally-substituted aryl(C₁–C₄ alkyl),the first heterocycle Y, Y—(C₁–C₄ alkyl), R⁷R⁸N—, and R⁷R⁸N—(C₂–C₄alkyl).

Illustrative compounds of formula I and II are described, wherein A is adisubstituted amino having the formula R⁵XN—, where R⁵ and X are takentogether with the attached nitrogen atom to form an heterocycle selectedfrom the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, andhomopiperazinyl;

-   -   where the heterocycle is optionally substituted with R¹⁰, R¹²,        R⁷R⁸N—, or R⁷R⁸N—(C₁–C₄ alkyl) as defined above.

Illustrative compounds of formula I and II are described, wherein R⁵ andX are taken together with the attached nitrogen atom to form piperidinyloptionally substituted at the 4-position with hydroxy, C₁–C₆ alkyl,C₃–C₈ cycloalkyl, C₁–C₄ alkoxy, (C₁–C₄ alkoxy)carbonyl, (hydroxy(C₂–C₄alkyloxy))-(C₂–C₄ alkyl), R⁷R⁸N—, R⁷R⁸N—(C₁–C₄ alkyl), diphenylmethyl,optionally-substituted aryl, optionally-substituted aryl(C₁–C₄ alkyl),or piperidin-1-yl(C₁–C₄ alkyl).

Illustrative compounds of formula I and II are described, wherein R⁵ andX are taken together with the attached nitrogen atom to form piperazinyloptionally substituted at the 4-position with C₁–C₆ alkyl, C₃–C₈cycloalkyl, optionally-substituted aryl, optionally-substitutedaryl(C₁–C₄ alkyl), α-methylbenzyl, N—(C₁–C₅ alkyl)acetamid-2-yl,N—(C₃–C₈ cycloalkyl)acetamid-2-yl, R⁷R⁸N—, or (C₁–C₄ alkoxy)carbonyl.

Illustrative compounds of formula I and II are described, wherein R⁵ andX are taken together with the attached nitrogen atom to formhomopiperazinyl optionally substituted in the 4-position with C₁–C₄alkyl, aryl, or aryl(C₁–C₄ alkyl).

Illustrative compounds of formula I and II are described, wherein A is adisubstituted amino having the formula R⁵XN—, where R⁵ and X are takentogether with the attached nitrogen atom to form an heterocycle selectedfrom the group consisting of pyrrolidinonyl, piperidinonyl,2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl,1,2,3,4-tetrahydroisoquinolin-2-yl.

Illustrative compounds of formula I are described, wherein A′ is anacyclic disubstituted amino.

Illustrative compounds of formula I are described, wherein A′ is acyclic disubstituted amino.

Illustrative compounds of formula I are described, wherein A′ is amonosubstituted amino having the formula X′NH—; where X′ is selectedfrom the group consisting of C₁–C₆ alkyl, C₃–C₈ cycloalkyl, (C₁–C₄alkoxy)-(C₁–C₄ alkyl), optionally-substituted aryl,optionally-substituted aryl(C₁–C₄ alkyl), the second heterocycle Y′,Y′—(C₁–C₄ alkyl), R^(7′)R^(8′)N—, and R^(7′)R^(8′)N—(C₂–C₄ alkyl).

Illustrative compounds of formula I are described, wherein A′ is adisubstituted amino having the formula R^(5′)X′N—; where R^(5′) isselected from the group consisting of hydroxy, C₁–C₆ alkyl, C₁–C₄alkoxycarbonyl, and benzyl; and X′ is selected from the group consistingof C₁–C₆ alkyl, C₃–C₈ cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄ alkyl),optionally-substituted aryl, optionally-substituted aryl(C₁–C₄ alkyl),the second heterocycle Y′, Y′—(C₁–C₄ alkyl), R^(7′)R^(8′)N—, andR^(7′)R^(8′)N—(C₂–C₄ alkyl).

Illustrative compounds of formula I are described, wherein A′ is adisubstituted amino having the formula R^(5′)X′N—, where R^(5′) and X′are taken together with the attached nitrogen atom to form anheterocycle selected from the group consisting of pyrrolidinyl,piperidinyl, piperazinyl, and homopiperazinyl;

-   -   where the heterocycle is optionally substituted with R¹⁰,        R^(12′), R^(7′)R^(8′)N—, or R^(7′)R^(8′)N—(C₁–C₄ alkyl) as        defined above.

Illustrative compounds of formula I are described, wherein R^(5′) and X′are taken together with the attached nitrogen atom to form piperidinyloptionally substituted at the 4-position with hydroxy, C₁–C₆ alkyl,C₃–C₈ cycloalkyl, C₁–C₄ alkoxy, (C₁–C₄ alkoxy)carbonyl, (hydroxy(C₁–C₄alkyloxy))-(C₁–C₄ alkyl), R^(7′)R^(8′)N—, R^(7′)R^(8′)N—(C₁–C₄ alkyl),diphenylmethyl, optionally-substituted aryl, optionally-substitutedaryl(C₁–C₄ alkyl), or piperidin-1-yl(C₁–C₄ alkyl).

Illustrative compounds of formula I are described, wherein R^(5′) and X′are taken together with the attached nitrogen atom to form piperazinyloptionally substituted at the 4-position with C₁–C₆ alkyl, C₃–C₈cycloalkyl, optionally-substituted aryl, optionally-substitutedaryl(C₁–C₄ alkyl), α-methylbenzyl, N—(C₁–C₅ alkyl)acetamid-2-yl,N—(C₃–C₈ cycloalkyl)acetamid-2-yl, R^(7′)R^(8′)N—, or (C₁–C₄alkoxy)carbonyl.

Illustrative compounds of formula I are described, wherein R^(5′) and X′are taken together with the attached nitrogen atom to formhomopiperazinyl optionally substituted in the 4-position with C₁–C₄alkyl, aryl, or aryl(C₁–C₄ alkyl).

Illustrative compounds of formula I are described, wherein A′ is adisubstituted amino having the formula R^(5′)X′N—, where R^(5′) and X′are taken together with the attached nitrogen atom to form anheterocycle selected from the group consisting of pyrrolidinonyl,piperidinonyl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl,1,2,3,4-tetrahydroisoquinolin-2-yl.

Illustrative compounds of formula I and II are described, wherein R⁴ isoptionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(C₂–C₄ alkenyl), or optionally-substituted aryl(C₂–C₄ alkynyl).

Illustrative compounds of formula I and II are described, wherein R³ isthe structure

Illustrative compounds of formula I and II are described, wherein R² ishydrogen.

Illustrative compounds of formula I and II are described, wherein A is adisubstituted amino having the formula R⁵XN—, where R⁵ and X are takentogether with the attached nitrogen atom to form an heterocycle selectedfrom the group consisting of pyrrolidinyl, piperidinyl, and piperazinyl;where said heterocycle is optionally substituted with C₁–C₆ alkyl, C₃–C₈cycloalkyl, R⁷R⁸N—, R⁷R⁸N—(C₁–C₄ alkyl), optionally-substituted aryl, oroptionally-substituted aryl(C₁–C₄ alkyl).

Illustrative compounds of formula I and II are described, wherein A is amonosubstituted amino having the formula XNH—, where X isoptionally-substituted aryl(C₁–C₄ alkyl).

Illustrative compounds of formula I and II are described, wherein:

R⁴ is optionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(C₂–C₄ alkenyl), or optionally-substituted aryl(C₂–C₄ alkynyl);

R³ is the structure

and,

R² is hydrogen.

Illustrative compounds of formula I are described, wherein A′ isR^(6′)O—, where R^(6′) is C₁–C₆ alkyl.

Illustrative compounds of formula I are described, wherein A′ is amonosubstituted amino having the formula X′NH—, where X′ isoptionally-substituted aryl(C₁–C₄ alkyl), the second heterocycle Y′,Y′—(C₁–C₄ alkyl), R^(7′)R^(8′)N—, or R^(7′)R^(8′)N—(C₂–C₄ alkyl).

Illustrative compounds of formula I are described, wherein X′ isR^(7′)R^(8′)N— or R^(7′)R^(8′)N—(C₂–C₄ alkyl).

Illustrative compounds of formula I are described, wherein X′ is thesecond heterocycle Y′ or Y′—(C₁–C₄ alkyl), where the second heterocycleY′ is selected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, and homopiperazinyl, where said secondheterocycle is optionally N-substituted with optionally-substitutedaryl(C₁–C₄ alkyl).

Illustrative compounds of formula I and II are described, wherein R^(8′)is selected from the group consisting of C₁–C₆ alkyl, C₃–C₈ cycloalkyl,and aryl(C₁–C₄ alkyl).

Illustrative compounds of formula I and II are described, wherein R^(7′)and R^(8′) are taken together with the attached nitrogen atom to form anheterocycle selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl, where saidpiperazinyl or homopiperazinyl is optionally substituted at the4-position with (C₁–C₄ alkyl), (C₃–C₈ cycloalkyl), or aryl(C₁–C₄ alkyl).

Illustrative compounds of formula I are described, wherein A′ is adisubstituted amino having the formula R^(5′)X′N—.

Illustrative compounds of formula I are described, wherein R^(5′) isaryl(C₁–C₄ alkyl), and X′ is selected from the group consisting ofoptionally-substituted aryl(C₁–C₄ alkyl), the second heterocycle Y′,Y′—(C₁–C₄ alkyl), R^(7′)R^(8′)N—, and R^(7′)R^(8′)N—(C₂–C₄ alkyl).

Illustrative compounds of formula I and II are described, wherein R^(8′)is selected from the group consisting of C₁–C₆ alkyl, C₃–C₈ cycloalkyl,and aryl(C₁–C₄ alkyl).

Illustrative compounds of formula I and II are described, wherein R^(7′)and R^(8′) are taken together with the attached nitrogen atom to form anheterocycle selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl, where saidpiperazinyl or homopiperazinyl is optionally substituted at the4-position with (C₁–C₄ alkyl), (C₃–C₈ cycloalkyl), or aryl(C₁–C₄ alkyl).

Illustrative compounds of formula I are described, wherein R^(5′) and X′are taken together with the attached nitrogen atom to form anheterocycle selected from the group consisting of pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, and homopiperazin-1-yl; where saidheterocycle is substituted with C₁–C₆ alkyl, C₃–C₈ cycloalkyl,optionally-substituted aryl, optionally-substituted aryl(C₁–C₄ alkyl),the second heterocycle Y′, Y′—(C₁–C₄ alkyl), R^(7′)R^(8′)N—,R^(7′)R^(8′)N—(C₁–C₄ alkyl), or R^(7′)R^(8′)N—C(O)—(C₁–C₄ alkyl).

Illustrative compounds of formula I are described, wherein R^(5′) and X′are taken together with the attached nitrogen atom to form anheterocycle selected from the group consisting of piperidin-1-yl andpiperazin-1-yl, where the heterocycle is substituted with C₁–C₆ alkyl,C₃–C₈ cycloalkyl, optionally-substituted aryl(C₁–C₄ alkyl),R^(7′)R^(8′)N—, or R^(7′)R^(8′)N—(C₁–C₄ alkyl).

Illustrative compounds of formula I and II are described, wherein R^(7′)and R^(8′) are taken together with the attached nitrogen atom to form anheterocycle selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl, where saidpiperazinyl or homopiperazinyl is optionally substituted at the4-position with (C₁–C₄ alkyl), (C₃–C₈ cycloalkyl), or aryl(C₁–C₄ alkyl).

Illustrative compounds of formula I are described, wherein R^(5′) and X′are taken together with the attached nitrogen to form piperazin-1-yl,where said piperazin-1-yl is substituted with C₁–C₆ alkyl, C₃–C₈cycloalkyl, or aryl(C₁–C₄ alkyl).

Illustrative compounds of formula I are described, wherein the integer nis 1.

Illustrative compounds of formula I are described, wherein the integer nis 2.

Illustrative compounds of formula II are described, wherein the integern′ is 1.

Illustrative compounds of formula II are described, wherein the integern′ is 2.

The present invention also describes a pharmaceutical comprising acompound selected from those described above, and a pharmaceuticallyacceptable carrier, diluent, or excipient.

The general chemical terms used in the formulae above have their usualmeanings. For example, the term “alkyl” includes such groups as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl and thelike.

The term “cycloalkyl” includes such groups as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term “alkenyl” includes such groups as ethenyl, propenyl, 2-butenyl,and the like.

The term “alkynyl” includes such groups as ethynyl, propynyl, 1-butynyl,and the like.

The term “aryl” refers to an aromatic ring or heteroaromatic ring andincludes such groups as furyl, pyrrolyl, thienyl, pyridinyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, phenyl,pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, oxadiazolyl,naphthyl, indanyl, fluorenyl, quinolinyl, isoquinolinyl, benzodioxanyl,benzofuranyl, benzothienyl, and the like.

The term “optionally-substituted” refers to the replacement of one ormore, preferably from one to three, hydrogen atoms with one or moresubstitutentss. Such substituents include such groups as C₁–C₄ alkyl,C₁–C₄ alkoxy, C₁–C₄ alkylthio, hydroxy, nitro, halo, carboxy, cyano,C₁–C₄ haloalkyl, C₁–C₄ haloalkoxy, amino, carboxamido, amino, mono(C₁–C₄alkyl)amino, di(C₁–C₄ alkyl)amino, C₁–C₄ alkylsulfonylamino, and thelike.

The term “heterocycle” refers to a saturated cyclic structure possessingone or more heteroatoms, such as nitrogen, oxygen, sulfur, and the like,and includes such groups as tetrahydrofuryl, morpholinyl, pyrrolidinyl,piperidinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.

The term “alkoxy” includes such groups as methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy and the like.

The terms “acyl” and “alkanoyl” include such groups as formyl, acetyl,propanoyl, butanoyl, pentanoyl and the like.

The term “halo” means fluoro, chloro, bromo, and iodo.

The term “alkanoyloxy” includes such groups as formyloxy, acetoxy,n-propionoxy, n-butyroxy, pivaloyloxy, and like lower alkanoyloxygroups.

The terms “optionally-substituted C₁–C₄ alkyl” and“optionally-substituted C₂–C₄ alkenyl” are taken to mean an alkyl oralkenyl chain which is optionally substituted with up to two methylgroups or with a C₁–C₄ alkoxycarbonyl group.

The term “(C₁–C₄ alkyl)” as used in for example “aryl(C₁–C₄ alkyl)”,“(C₁–C₄ alkoxy)-(C₁–C₄ alkyl)”, and the like, refers to a saturatedlinear or branched divalent alkyl chain of from one to four carbonsbearing for example aryl, C₁–C₄ alkoxy, and the like, as a substituentand includes such groups as for example benzyl, phenethyl, phenpropyl,α-methylbenzyl, methoxymethyl, ethoxyethyl, and the like.

The term “optionally-substituted phenyl” is taken to mean a phenylradical optionally substituted with one or two substituentsindependently selected from the group consisting of C₁–C₄ alkyl, C₁–C₄alkoxy, hydroxy, halo, nitro, trifluoromethyl, sulfonamido, cyano,carbamoyl, amino, mono(C₁–C₄ alkyl)amino, di(C₁–C₄ alkyl)amino, C₁–C₄alkylsulfonylamino, and indol-2-yl.

The term “protected amino” refers to amine protecting groups used toprotect the nitrogen of the β-lactam ring during preparation orsubsequent reactions. Examples of such groups are benzyl,4-methoxybenzyl, 4-methoxyphenyl, or trialkylsilyl, for exampletrimethylsilyl.

The term “protected carboxy” refers to the carboxy group protected orblocked by a conventional protecting group commonly used for thetemporary blocking of the acidic carboxy. Examples of such groupsinclude lower alkyl, for example tert-butyl, halo-substituted loweralkyl, for example 2-iodoethyl and 2,2,2-trichloroethyl, benzyl andsubstituted benzyl, for example 4-methoxybenzyl and 4-nitrobenzyl,diphenylmethyl, alkenyl, for example allyl, trialkylsilyl, for exampletrimethylsilyl and tert-butyldiethylsilyl and like carboxy-protectinggroups.

The term “antagonist”, as it is used in the description of thisinvention, is taken to mean a full or partial antagonist. A compoundwhich is a partial antagonist at the vasopressin V_(1a) receptor mustexhibit sufficient antagonist activity to inhibit the effects ofvasopressin or a vasopressin agonist at an acceptable dose. While apartial antagonist of any intrinsic activity may be useful, partialantagonists of at least about 50% antagonist effect are preferred andpartial antagonists of at least about 80% antagonist effect are morepreferred. Full antagonists of the vasopressin V_(1a) receptor are mostpreferred.

DETAILED DESCRIPTION OF THE INVENTION

Certain classes of compounds of the present invention having formula Ior formula II are preferred. Illustrative classes of such compounds aredescribed in the following paragraphs.

A class of compounds having formula I, wherein:

(aa) A is R⁶O—;

(ab) R⁶ is C₁–C₆ alkyl;

(ac) R⁶ is optionally-substituted aryl(C₁–C₄ alkyl);

(ad) A is a monosubstituted amino of the formula XNH—;

(ae) A is a disubstituted amino having the formula R⁵XN—;

(af) A′ is a monosubstituted amino having the formula X′NH—;

(ag) A′ is a disubstituted amino having the formula R^(5′)X′N—;

(ah) A′ is R^(6′)O—;

(ai) R^(6′) is C₁–C₆ alkyl;

(aj) R^(6′) is optionally-substituted aryl(C₁–C₄ alkyl);

(ak) X is optionally-substituted aryl(C₁–C₄ alkyl);

(al) X is R⁷R⁸N—(C₁–C₄ alkyl);

(am) R⁷ and R⁸ are taken together with the attached nitrogen atom toform an heterocycle;

(an) R⁵ and X are taken together with the attached nitrogen atom to forman heterocycle;

(ao) the heterocycle is optionally substituted with anoptionally-substituted aryl(C₁–C₄ alkyl), the first heterocycle Y, orC₃–C₈ cycloalkyl;

(ap) R² is hydrogen;

(aq) R² is C₁–C₆ alkyl;

(ar) R² is C₁–C₂ alkyl;

(as) R³ is 4-substituted oxazolidin-2-on-3-yl;

(at) R³ is 4,5-disubstituted oxazolidin-2-on-3-yl;

(au) R³ is 2-substituted oxazolidin-4-on-3-yl;

(av) R³ is 2-substituted imidazolidin-4-on-3-yl;

(aw) R³ is 1,2-disubstituted imidazolidin-4-on-3-yl;

(ax) R³ is 5-substituted imidazolidin-2-on-1-yl;

(ay) R³ is 4,5-disubstituted imidazolidin-4-on-1-yl;

(az) R⁴ is optionally-substituted 2-aryleth-1-yl;

(ba) R⁴ is optionally-substituted 2-arylethen-1-yl;

(bb) R^(5′) is benzyl;

(bc) X′ is the heterocycle Y;

(bd) X is optionally-substituted aryl(C₁–C₄ alkyl);

(be) aryl is optionally-substituted phenyl;

(bf) X′ is R^(7′)R^(8′)N—(C₁–C₄ alkyl);

(bg) X′ is R^(7′)R^(8′)N—;

(bh) R^(7′) is C₁–C₆ alkyl;

(bi) R^(8′) is C₁–C₆ alkyl;

(bj) R⁷ and R⁸ are taken together with the attached nitrogen atom toform an heterocycle;

(bk) R⁷ and R⁸ are the same and are C₁–C₆ alkyl;

(bl) R^(5′) and X′ taken together with the nitrogen to which they areattached form pyrrolidinyl, piperidinyl, piperazinyl; where saidpyrrolidinyl, piperidinyl, or piperazinyl is optionally substituted withthe second heterocycle Y′ or with R⁷R⁸N—(C₁–C₄ alkyl);

(bm) R^(5′) and X′ taken together with the nitrogen to which they areattached form piperidinyl optionally substituted at the 4-position withhydroxy, C₁–C₆ alkyl, C₃–C₈ cycloalkyl, C₁–C₄ alkoxy, (C₁–C₄alkoxy)carbonyl, (hydroxy(C₁–C₄ alkyloxy))-(C₁–C₄ alkyl), R⁷R⁸N—,R⁷R⁸N—(C₁–C₄ alkyl), phenyl, phenyl(C₁–C₄ alkyl), optionally-substitutedphenyl(C₁–C₄ alkyl), furyl(C₁–C₄ alkyl), pyridinyl(C₁–C₄ alkyl),thienyl(C₁–C₄ alkyl), or piperidin-1-yl(C₁–C₄ alkyl);

(bn) R^(5′) and X′ taken together with the nitrogen to which they areattached form piperazinyl optionally substituted at the 4-position withC₁–C₆ alkyl, C₃–C₈ cycloalkyl, optionally-substituted phenyl,optionally-substituted phenyl(C₁–C₄ alkyl), N—(C₁–C₅alkyl)acetamid-2-yl, N—(C₃–C₈ cycloalkyl)acetamid-2-yl, R⁷R⁸N—, or(C₁–C₄ alkoxy)carbonyl; and

(bo) R^(5′) and X′ taken together with the nitrogen to which they areattached form homopiperazinyl optionally substituted in the 4-positionwith C₁–C₄ alkyl, phenyl, or phenyl(C₁–C₄ alkyl).

It is appreciated that the classes of compounds described above may becombined to form additional illustrative classes. An example of such acombination of calsses may be a class of compounds wherein A is amonosubstituted amino having the formula XNH—, where X isoptionally-substitued aryl(C₁–C₄ alkyl), and A′ is a disubstituted aminohaving the formula R^(5′)X′N—, where R^(5′) and X′ are taken togetherwith the attached nitrogen atom to form an heterocycle, such aspiperidine, peperazine, and the like. Further combinations of theclasses of compounds described above are contemplated in the presentinvention.

Further illustrative classes of compounds are described by compoundshaving formula III:

wherein:

Ar is optionally-substituted phenyl, optionally-substituted pyridinyl,optionally-substituted furyl, or optionally-substituted thienyl;

R² is hydrogen;

A is XNH—;

A′ is X′NH—;

A′ is R^(5′)X′N—;

n is 0, 1, or 2;

X is optionally-substituted aryl(C₁–C₄ alkyl), and aryl is substitutedphenyl;

A′ is R^(6′)O—;

R⁶′ is C₁–C₆ alkyl;

X′ is R^(7′)R^(8′)N—;

X′ is optionally-substituted aryl(C₁–C₄ alkyl);

X′ is the second heterocycle Y′;

R^(5′) and X′ are taken together with the attached nitrogen atom to formpiperidinyl, piperazinyl, or homopiperazinyl; where said piperidinyl,piperazinyl, or homopiperazinyl is optionally substituted with C₁–C₆alkyl, C₃–C₈ cycloalkyl, the second heterocycle Y′,optionally-substituted aryl(C₁–C₄ alkyl), R⁷R⁸N—, R⁷R⁸N—(C₁–C₄ alkyl),or R⁷R⁸N—C(O)—(C₁–C₄ alkyl);

R^(8′) is C₁–C₆ alkyl, C₃–C₈ cycloalkyl, optionally-substituted aryl,optionally-substituted aryl(C₁–C₄ alkyl); and

R^(7′) and R^(8′) are taken together with the attached nitrogen atom toform an heterocycle selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, and piperazinyl; where said piperazinyl isoptionally substitued at the 4-position with C₁–C₄ alkyl.

Further illustrative classes of compounds are described by compoundshaving formula IV:

wherein:

Ar is optionally-substituted phenyl, optionally-substituted pyridinyl,optionally-substituted furyl, or optionally-substituted thienyl;

R² is hydrogen;

A is XNH—;

n′ is 1, 2, or 3;

X is optionally-substituted aryl(C₁–C₄ alkyl), and aryl is substitutedphenyl;

R^(6′) is

R^(8′) is C₁–C₆ alkyl, C₃–C₈ cycloalkyl, optionally-substituted aryl,optionally-substituted aryl(C₁–C₄ alkyl); and

R^(7′) and R^(8′) are taken together with the attached nitrogen atom toform an heterocycle selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, and piperazinyl; where said piperazinyl isoptionally substitued at the 4-position with C₁–C₄ alkyl.

The following Tables 1–5 are illustrative of compounds contemplated tobe within the scope of the present invention.

TABLE 1 2-[3-(Oxazolidin-2-on-3-yl)azetidinon-1-yl]alkanedioic acidderivatives.

n R² R¹⁰ R¹¹ A A′ Ar 0 H benzofur-2-yl 3-iodophenyl2-(piperidin-1-yl)ethylamino 4-(pyrrolidin-1-yl)piperazin-1-yl fur-3-yl0 methyl benzofur-7-yl 4-fluorophenyl 4-(piperidin-1-yl)piperidin-1-yl4-(3-trifluorophenyl)piperazin-1-yl pyrrol-2-yl 0 ethyl benzothien-5-yl4-cyanophenyl 4-(phenylethyl)piperazin-1-yl4-(benzyloxycarbonyl)piperazin- pyrrol-3-yl 1-yl 1 methylbenzothien-3-yl phenyl fur-2-ylmethylamino 4-[2-(2-hydroxyethoxy)ethyl]-pyridin-2-yl piperazin-1-yl 1 H thien-2-yl methoxycarbonyl4-(3-trifluoromethylphenyl)- 4-(3,4-methylenedioxybenzyl)- pyridin-4-ylpiperazin-1-yl piperazin-1-yl 1 H naphth-2-yl 4-ethylaminophenyl4-(benzyloxycarbonyl)piperazin- 4-phenylpiperazin-1-yl thiazol-2-yl 1-yl2 methyl 3-phenyprop-1- 2-isobutoxycarbonyl 4-[2-(2-hydroxyethyl)ethyl]-4-(3-phenylprop-2-enyl)piperazin- thiazol-4-yl yl piperazin-1-yl 1-yl 2ethyl 2-pheneth-1-yl 2-methanesulfonyl- 4-benzylpiperazin-1-yl4-ethylpiperazin-1-yl thiazol-5-yl aminophenyl 2 methyl3-isopropylbenzyl cyclohexyl 4-(3,4-methylenedioxybenzyl)-2-(dimethylamino)ethylamino oxazol-2-yl piperazin-1-yl

TABLE 2 2-[3-(Oxazolidin-4-on-3-yl)azetidinon-1-yl]alkanedioic acidderivatives.

n R² R¹⁰ A A′ Ar 0 ethyl 4-fluorobenzyl 4-phenylpiperazin-1-yl4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl oxazol-4-yl 0 H benzyl4-(3-phenylprop-2-enyl)piperazin-1-yl4-(1-methylpiperidin-4-yl)piperazin-1-yl oxazol-5-yl 0 methyl4-methoxyphenyl 4-ethylpiperazin-1-yl 4-butylpiperazin-1-ylisoxazol-3-yl 1 H 3-chlorophenyl 2-(dimethylamino)ethylamino4-isopropylpiperazin-1-yl isoxazol-4-yl 1 methyl 2-ethylphenyl4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl2-(piperidin-1-yl)ethylamino isoxazol-5-yl 1 ethyl phenyl4-(1-methylpiperidin-4-yl)piperazin-1-yl 4-(2-phenylethyl)piperazin-1-ylimidazol-2-yl 1 methyl cyclopropyl 4-butylpiperazin-1-yl4-(piperidin-1-yl)piperidin-1-yl imidazol-4-yl 2 H cyclobutyl4-isopropylpiperazin-1-yl 2-(pyridin-2-yl)ethylamino imidazol-5-yl 2 Hcyclopentyl 4-pyridylmethylamino morpholin-4-ylamino pyrazol-3-yl 2 Hcyclohexyl 3-(dimethylamino)propylamino4-(pyrrolidin-1-yl)piperazin-1-yl pyrazol-4-yl

TABLE 3 2-[3-(Succinimid-1-yl)azetidinon-1-yl]alkanedioic acidderivatives.

n R² R¹¹ A A′ Ar 0 H naphth-2-yl 1-benzylpiperidin-4-ylamino4-(3-trifluorophenyl)piperazin-1-yl pyrazol-5-yl 0 ethyl propylN-benzyl-2-(dimethylamino)ethylamino 4-(benzyloxycarbonyl)piperazin-1-ylpyrimidin-2-yl 0 methyl 3-chloronaphth-1-yl 3-pyridylmethylamino4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl pyrimidin-4-yl 1 ethyl ethyl4-(cyclohexyl)piperazin-1-yl 4-benzylpiperazin-1-yl Pyrimidin-5-yl 1 H6-methoxynaphth-2-yl 4-(2-cyclohexylethyl)piperazin-1-yl4-(3,4-methylenedioxybenzyl)piperazin 1-yl Thiadiazol-3-yl 1 methylmethyl 4-[2-(morpholin-4-yl)ethyl]piperazin-1-yl 4-phenylpiperazin-1-ylOxadiazol-3-yl 1 H 5-aminonaphth-1-yl4-(4-tert-butylbenzyl)piperazin-1-yl4-(3-phenylprop-2-enyl)piperazin-1-yl Quinolin-2-yl 2 methylethoxycarbonyl 4-[2-(piperidin-1-yl)ethyl]piperazin-1-yl4-ethylpiperazin-1-yl Quinolin-3-yl 2 ethyl isopropyl4-[3-(piperidin-1-yl)propyl]piperazin-1-yl 2-(dimethylamino)ethylaminoQuinolin-4-yl 2 methyl tert-butoxycarbonyl4-[2-(N,N-dipropylamino)ethyl]piperazin-1-yl4-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl Isoquinolin-1- yl

TABLE 4 2-[3-(Imidazol-2-on-1-yl)azetidinon-1-yl]alkanedioic acidderivatives.

n R² R¹⁰ R¹¹ R¹² A A′ Ar 0 H 3-nitrophenyl propyl tert-butoxycarbonyl4-[3-(N,N- 4-(1-methylpiperidin-4- naphth-1-yl diethylamino)propyl]-yl)piperazin-1-yl piperazin-1-yl 0 ethyl 3-(thiobenzyl)- naphth-1-ylbenzyloxycarbonyl 4-[2-(dimethylamino)- 4-butylpiperazin-1-ylnaphth-2-yl prop-1-yl ethyl]piperazin-1-yl 0 methyl Phenoxycarbonylethyl H 4-[3-(pyrrolidin-1- 4-isopropylpiperazin-1-yl 2-fluorophenylyl)propyl]piperazin-1-yl 1 methyl 2-methoxycar- naphth-2-yl4-isopropylbenzyloxy- 4-(cyclohexylmethyl)- 4-pyridylmethylamino3-chlorophenyl bonyl-ethyl carbonyl piperazin-1-yl 1 ethyl 4-methanesul-methyl 3-methoxybenzyloxy- 4-cyclopentylpiperazin- 3-(dimethylamino)-4-bromophenyl fonylphenyl carbonyl 1-yl propylamino 1 H Isopropyl2-chloronaphth- 2-butoxybenzyloxy- 4-[2-(pyrrolidin-1-1-benzylpiperidin-4- 2-methylphenyl 1-yl carbonylyl)ethyl]piperazin-1-yl ylamino 1 ethyl 3-aminophenyl 6-methoxynaphth-3-chlorobenzyloxy- 4-[2-(thien-2- N-benzyl-2- 3-isopropylphenyl 2-ylcarbonyl yl)ethyl]piperazin-1-yl (dimethylamino)- ethylamino 2 H2-cyanophenyl isobutyl 3-fluoro-5- 4-(3-phenylpropyl)-3-pyridylmethylamino 2-propoxyphenyl methoxybenzyloxy- piperazin-1-ylcarbonyl 2 methyl 3-methylthiobutyl 5-aminonaphth-1-yl 3-cyanobenzyloxy-4-[2-(N,N-diethylamino)- 4-cyclohexylpiperazin- 3-methoxyphenyl carbonylethyl]piperazin-1-yl 1-yl 2 H 4-hydroxyphenyl butyl methyl4-benzylhomopiperazin- 4-(2-cyclohexylethyl)- 2-ethylthiophenyl 1-ylpiperazin-1-yl

TABLE 5 2-[3-(Imidazol-5-on-1-yl)azetidinon-1-yl]alkanedioic acidderivatives.

n R² R¹⁰ R¹² A A′ Ar 0 methyl 2-fluoro-4- 3-aminobenzyloxycarbonyl4-(bisphenylmethyl)piperazin- 4-[2-(morpholin-4- 4-methyl- methoxyphenyl1-yl yl)ethyl]piperazin-1-yl thiophenyl 0 ethyl 3-ethoxyphenyl2-hydroxybenzyloxycarbonyl 3-(4-methylpiperazin-1-4-(4-tert-butylbenzyl)- 2-nitrophenyl yl)propylamino piperazin-1-yl 0methyl 2-methylphenyl 3-ethylaminobenzyloxy-(+)-3(S)-1-benzylpyrrolidin- 4-[2-(piperidin-1- 2-carboxyphenyl carbonyl3-ylamino yl)ethyl]piperazin-1-yl 1 H 2-methoxyphenyl4-dimethylaminobenzyloxy- 2-pyridylmethylamino 4-[3-(piperidin-1-3-carboxamido- carbonyl yl)propyl]piperazin-1-yl phenyl 1 H3-ethoxyphenyl methyl 4-ethylpiperazin-1-yl 4-[2-(diisopropylamino)-2,3-difluorophenyl ethyl]piperazin-1-yl 1 H 3-isopropylphenyl benzyl2-(dimethylamino)ethylamino 4-[3-(diethylamino)- 3,5-dichlorophenylpropyl]piperazin-1-yl 1 H 4-chlorophenyl isopropoxycarbonyl4-(pyrrolidin-1- 4-(2-dimethylaminoethyl)- 3-chloro-4-ylcarbonylmethyl)- piperazin-1-yl bromophenyl piperazin-1-yl 2 ethyl2-chloro-4- propoxycarbonyl 4-(1-methylpiperidin-4- 4-[3-(pyrrolidin-1-5,6-dichloro-3- bromophenyl yl)piperazin-1-yl yl)propyl]piperazin-1-yliodophenyl 2 H 2-ethyl-3- ethoxycarbonyl 4-butylpiperazin-1-yl4-(cyclohexylmethyl) 2,4-dimethylphenyl bromophenyl piperazin-1-yl 2ethyl 2-chloro-4- methoxycarbonyl 4-isopropyl0piperazin-1-yl4-(2-dimethylaminoethyl)- 3-methyl-4- bromophenyl piperazin-1-ylisopropoxyphenyl

The compounds of the present invention are comprised of an azetidinonenucleus, said nucleus bearing asymmetric carbons at the 3- and4-positions as illustrated by following structures:

The compounds of the invention may, therefore, exist as singlediastereomers, mixtures of diastereomers, or as a racemic mixture, allof which are useful and part of the invention. It is preferred that theazetidinone nucleus of the compounds of the invention exist in a singlediastereomeric form. It is most preferred that the azetidinone nucleusexist as the (3S,4R)-diastereomer.

It is appreciated that, except when A=A′ and n=0, the carbon bearing R²is also asymmetric. Furthermore, when R³ is 4-substitutedoxazolidin-2-on-3-yl, the 4-position of that ring is asymmetric. Inaddition, when R³ is 2,5-disubstituted oxazolidin-4-on-3-yl or1,2,5-trisubstituted imidazolidin-4-on-3-yl, the 2- and 5-carbons ofthose rings are asymmetric. Finally, when R³ is succinimido and one ofR¹⁴ and R¹⁵ is hydrogen, the carbon bearing the non-hydrogen substituentis also asymmetric. While compounds possessing all combinations ofstereochemical purity are contemplated by the present invention, it isappreciated that in many cases at least one of these chiral centersdescribed above may be present in a single absolute configuration.

The compounds of this invention are useful in methods for antagonism ofthe vasopressin V_(1a) receptor. Such antagonism is useful in treating avariety of disorders that have been linked to this receptor in mammals.It is preferred that the mammal to be treated by the administration ofcompounds of this invention is human.

Since certain of the compounds of this invention are amines, they arebasic in nature and accordingly react with any of a number of inorganicand organic acids to form pharmaceutically acceptable acid additionsalts. Because some of the free amines of the compounds of thisinvention are typically oils at room temperature, it is preferable toconvert the free amines to their pharmaceutically acceptable acidaddition salts for ease of handling and administration, since the latterare routinely solid at room temperature. Acids commonly employed to formsuch salts are inorganic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, andorganic acids, such as p-toluenesulfonic acid, methanesulfonic acid,oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid,citric acid, benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable salts are those formed with hydrochloricacid, trifluoroacetic acid, maleic acid or fumaric acid.

The 2-(azetidinon-1-yl)alkanedioic acid esters and amides of formulae Iand II are prepared by syntheses well known in the art. As illustratedfor compounds of formula I, the 2-(azetidinon-1-yl)alkanedioic acidesters are obtainable by the 2+2 cycloaddition of an appropriatelysubstituted acetic acid derivative (i), and an imine ester (ii) asdescribed in Synthetic Scheme I, where Z is a leaving group, and theinteger n, and the moieties A, A′, R², R³, and R⁴ are as previouslydescribed. The term “leaving group” as used hereinafter refers to asubsitutent, such as halo, acyloxy, benzoyloxy and the like, present onan activated carbon atom that may be replaced by a nucleophile. Thechemistry described in Synthetic Scheme I is applicable to imines (ii)bearing ester, thioester, or amide moieties.

Synthetic Scheme I

The preparation of the appropriate imines (ii) and most of the requiredacetyl halides or anhydrides (i), as well as the cycloadditionprocedure, are generally described in U.S. Pat. Nos. 4,665,171 and4,751,299, hereby incorporated by reference. The analogous synthesis ofcompounds of formula II may be accomplished by this process using theappropriate alkoxy-substituted amino acid imines.

Those compounds of formulae I and II of the invention requiring R³ to be4-substituted oxazolidin-2-on-3-yl or 1,4,5-trisubstitutedimidazolidin-2-on-3-yl are prepared from the corresponding(4-substituted oxazolidin-2-on-3-yl)- or (1,4,5-trisubstitutedimidazolidin-2-on-3-yl)-acetyl halide or anhydride. The acid halide oranhydride is available from an appropriately substituted glycine. Theglycine is first converted to the carbamate and then reduced to providethe corresponding alcohol. The alcohol is then cyclized to the4-substituted oxazolidin-2-one, which is subsequently N-alkylated with ahaloacetic acid ester. The ester is hydrolyzed, and the resulting acidis converted to the acetyl halide or anhydride (i).

Those compounds of the invention requiring R³ to be 2,5-disubstitutedoxazolidin-4-on-3-yl or 1,2,5-trisubstituted imidazolidin-4-on-3-yl areprepared from the corresponding (2,5-disubstitutedoxazolidin-4-on-3-yl)- or (1,2,5-trisubstitutedimidazolidin-4-on-3-yl)acetyl chlorides or anhydrides respectively. Thechemistry to prepare these reagents is described in U.S. Pat. No.4,772,694, hereby incorporated by reference. Briefly, the requiredoxazolidinone or imidazolidinone is obtained from an α-hydroxyacid or anα-aminoacid, respectively. The imidazolones are prepared by convertingthe α-aminoacid, (R¹¹)—CH(NH₂)CO₂H, to an amino-protected amide and thencondensing the amide with an aldehyde, (R¹⁰)—CHO, in the presence of anacid to form the 3-protected imidazolidin-4-one, where R¹⁰ and R¹¹ areas defined above. The 1-position may be functionalized with anappropriate reagent to introduce R¹² and the 3-position deprotected,where R¹² is as defined above. The imidazolidin-4-one ring is thenalkylated with a haloacetic acid ester, the ester deesterified, and theresulting acetic acid converted to the desired acid halide or anhydride(i). The required oxazolidinones are prepared in an analogous mannerfrom the corresponding α-hydroxyacid, (R¹¹)—CH(OH)CO₂H.

Those compounds of the invention requiring R³ to be succinimido areprepared from the corresponding 2-(succinimido)acetyl halide oranhydride. The chemistry to prepare these reagents is described in U.S.Pat. No. 4,734,498, hereby incorporated by reference. Briefly, thesereagents are obtained from tartaric acid or, when one of R¹⁰ and R¹¹ ishydrogen, from malic acid. Tartaric acid is acylated or O-alkylated, thecorresponding diacyl or di-O-alkyl tartaric acid is treated with an acidanhydride to form the succinic anhydride, and reaction of this succinicanhydride with an ester of glycine to form first the noncyclic halfamide ester which is then cyclized to the 3,4-disubstitutedsuccinimidoacetic acid ester. The ester group is deesterified and theresulting acid converted to the corresponding acid halide or anhydride(i). The mono-substituted succinimidoacetyl halide or anhydride isobtained with malic acid via succinic anhydride formation followed bysuccinimide formation as described above.

Those compounds of the invention requiring R³ to be an N-substitutedamine or an N′-substituted urea may be prepared from the correspondingphthalimido protected 3-amino analogs. The phthalimide protecting groupmay be removed using conventional procedures, such as by treatment withhydrazine, and the like. Once liberated, the amine may be alkylated withany one of a variety of alkyl and cycloalkyl halides and sulfates, suchas methyl iodide, isopropylbromide, diethyl sulfate,cyclopropylmethylbromide, cyclopentyliodide, and the like. Such aminesmay also be acylated with acid halides, acid anhydrides, isocyanates,isothiocyanates, such as acetyl chloride, propionic anhydride,methylisocyanate, 3-trifluoromethylphenylisothiocyanate, and the like.

The bases to be used in Synthetic Scheme I include, among others,aliphatic tertiary amines, such as trimethylamine and triethylamine,cyclic tertiary amines, such as N-methylpiperidine andN-methylmorpholine, aromatic amines, such as pyridine and lutidine, andother organic bases such as 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).

The solvents useful for reactions described in Synthetic Scheme Iinclude, among others, dioxane, tetrahydrofuran, diethyl ether, ethylacetate, dichloromethane, chloroform, carbon tetrachloride, benzene,toluene, acetonitrile, dimethyl sulfoxide and N,N-dimethylformamide.

Alternatively, the compounds of formulae I and II may be prepared viaN—C(4) cyclization, as illustrated for compounds of formula I inSynthetic Scheme II, via cyclizatoin of β-hydroxy amides iii, where R²,R³, R⁴, A, and A′ are as defined previously, according to the procedureof Townsend and Nguyen in J. Am. Chem. Soc. 1981, 103, 4582, and Millerand Mattingly in Tetra. 1983, 39, 2563, the disclosures of which areincorporated herein by reference. The analogous synthesis of compoundsof formula II may be accomplished by cyclizatoin of β-hydroxy amides ofalkoxy-substituted amino acids.

Synthetic Scheme II

The azetidinone ring may also be prepared with a deficit of substituentsR³, R⁴, or the R²-substituted N-alkanedioic acid or alkoxyalkanoic acidmoiety, but possessing substituents capable of being elaborated throughsubsequent chemical transformation to such groups described forcompounds of formulae I and II. In general, azetidinones may be preparedvia N—C(4) cyclization, such as the cyclization of acylhydroxamates ivto azetidinone intermediates v, as depicted in Scheme III, where R², R³,R⁴, A, and A′ are as defined above, according to the procedure ofMattingly et al. in J. Am. Chem. Soc. 1979, 101, 3983 and Accts. Chem.Res. 1986, 19, 49, the disclosures of which are incorporated herein byreference. It is appreciated that other hydroxamates, such asalkylhydroxamates, aryl hydroxamates, and the like, are suitable forcarrying out the cyclization.

Synthetic Scheme III

Subsequent chemical transformation of the acyloxyazetidinone v tointroduce for example an R²-substituted alkanedioic acid moiety usingconventional procedures will illustratively provide compounds of formulaI. The analogous synthesis of compounds of formula II may beaccomplished by this process using an appropriate R²-substitutedalkoxyalkanoic acid.

An alternative cyclization to form intermediate azetidinones, which maybe further elaborated to compounds of formulae I and II, may occur byoxidative cyclization of acylhydroxamates vi to intermediateazetidinones vii, as illustrated in Synthetic Scheme IV, where R³ is asdefined above, according to the procedure of Rajendra and Miller in J.Org. Chem. 1987, 52, 4471 and Tetrahedron Lett. 1985, 26, 5385, thedisclosures of which are incorporated herein by reference. The group Rin Scheme IV represents an alkyl or aryl moiety selected to provide R⁴,as defined above, upon subsequent transformation. For example, R may bethe group PhCH₂—, as in vii-a, such that oxidative elimination of HBrwill provide the desired R⁴, a styryl group, as in vii-b. It isappreciated that elaboration of R to R⁴ is not necessarily performedimmediately subsequent to the cyclization and may be performedconveniently after other steps in the synthesis of compounds of formulaeI and II. It is further appreciated that alternatives to theacylhydroxamates shown, such as alkylhydroxamates, aryl hydroxamates,and the like, are suitable for carrying out the cyclization.

Synthetic Scheme IV

Other useful intermediates, such as the azetidinone-4-carboxaldehydeviii illustrated in Synthetic Scheme V for preparing for examplecompounds of formula I, may be further elaborated to 4-(R⁴)-substitutedazetidinones via an olefination reaction. The group R in Scheme V isselected such that upon successful olefination of the carboxaldehyde theresulting group R—CHCH— corresponds to the desired alkyl or aryl moietyR⁴, as defined above. Such olefination reactions may be accomplished byany of the variety of known procedures, such as by Wittig olefination,Peterson olefination, and the like. Synthetic Scheme V illustrates thecorresponding Wittig olefination with phosphorane ix. The analogoussynthesis of compounds of formula II may be accomplished by this processusing an appropriate alkoxy-substituted azetidinone-4-carboxaldehydederivative.

Synthetic Scheme V

Still other useful intermediates, such as the azetidinonyl acetic acidderivatives x, may be converted into compounds of formulae I and II, asillustrated for the synthesis of compounds of formula I in SyntheticScheme VI. Introduction of an R² moiety, and a carboxylic acidderivative A′-C(O)—(CH₂)_(n)— for compounds of formula I, or analkoxyalkanoic acid derivative R^(6′)O—(CH₂)_(n)— for compounds offormula II, may be accomplished by alkylation of the anion of x, wherethe integers n and n′, and the groups R², R³, R⁴, R^(6′), A, and A′ areas defined above.

Synthetic Scheme VI

Acetic acid derivative x is deprotonated and subsequently alkylated withan alkyl halide corresponding to R²-Z, where Z is a leaving group, toprovide intermediate xi. Illustratively, the anion of xi may bealkylated with a compound Z′-(CH₂)_(n)COA′, where Z′ is a leaving group,to provide compounds of formula I. It is appreciated that the order ofintroduction of either the substituent R² or the acid derivative—(CH₂)_(n)COA′, or the alkoxyalkanoic acid derivative—(CH₂)_(n′)OR^(6′), is conveniently chosen by the skilled artisan andsuch order of introduction may be different for each compound of formulaI or formula II.

A solution of the 2-(3,4-disubstituted azetidin-2-on-1-yl)acetic acidderivative x or xi in an appropriate solvent, such as tetrahydrofuran,dioxane, or diethyl ether, is treated with a non-nucleophilic base togenerate the anion of x or xi, respectively. Suitable bases for thistransformation include lithium diisopropylamide, lithium2,2,6,6-tetramethylpiperidinamide, or lithium bis(trimethylsilyl)amide.The anion is then quenched with an appropriate electrophile to providethe desired compounds. Illustrative electrophiles represented by theformulae R²-Z, R^(5′)X′N—C(O)—(CH₂)_(n)-Z, or R^(6′)O—C(O)—(CH₂)_(n)-Zprovide the corresponding compounds xi or I, respectively. The analogoussynthesis of compounds of formula II may be accomplished by this processby using an electrophile represented by the formula R^(6′)O—(CH₂)_(n)-Z.

As discussed above, the compounds prepared as described in SyntheticSchemes I, II, III, IV, V, and VI may be pure diastereomers, mixtures ofdiastereomers, or racemates. The actual stereochemical composition ofthe compound will be dictated by the specific reaction conditions,combination of substituents, and stereochemistry of the reactantsemployed. It is appreciated that diasteromeric mixtures may be separatedby chromatography or fractional crystallization to provide singlediastereomers if desired. Particularly, the reactions described inSynthetic Schemes III, IV, and VI create a new chiral center at thecarbon bearing R², except when n=0 and A=A′.

Compounds of formula I which are 2-(3,4-disubstitutedazetidin-2-on-1-yl)alkanedioic acid half-esters, such as compounds I-awhere A′ is R^(6′)O—, while useful vasopressin V_(1a) agents in theirown right, may also be converted to the corresponding half-carboxylicacids xii, where the integer n and the groups R², R³, R⁴, R^(5′),R^(6′), A, and X′ are as previously defined, as illustrated in SyntheticScheme VII. These intermediates are useful for the preparation of othercompounds of the invention, such as I-b where A′ is R^(5′)X′N—. It isappreciated that the transformation illustrated in Synthetic Scheme VIIis equally applicable for the preparation of compounds I where A′ isX′NH— or where a different R^(6′)O— is desired.

Synthetic Scheme VII

The requisite carboxylic acid xii may be prepared from the correspondingester via saponification under standard conditions by treatment withhydroxide followed by protonation of the resultant carboxylate anion.Where R^(6′) is tert-butyl, the ester I-a may be dealkylated bytreatment with trifluoroacetic acid. Where R^(6′) is benzyl, the esterI-a may be dealkylated either by subjection to mild hydrogenolysisconditions, or by reaction with elemental sodium or lithium in liquidammonia. Finally, where R^(6′) is 2-(trimethylsilyl)ethyl, the ester I-amay be deprotected and converted into the corresponding acid xii bytreatment with a source of fluoride ion, such as tetrabutylammoniumfluoride. The choice of conditions is dependent upon the nature of theR^(6′) moiety and the compatability of other functionality in themolecule with the reaction conditions.

The carboxylic acid xii is converted to the corresponding amide I-bunder standard conditions well recognized in the art. The acid may befirst converted to the corresponding acid halide, preferably thechloride or fluoride, followed by treatment with an appropriate primaryor secondary amine to provide the corresponding amide. Alternatively,the acid may be converted under standard conditions to a mixedanhydride. This is typically accomplished by first treating thecarboxylic acid with an amine, such as triethylamine, to provide thecorresponding carboxylate anion. This carboxylate is then reacted with asuitable haloformate, for example benzyl chloroformate, ethylchloroformate or isobutylchloroformate, to provide the correspondingmixed anhydride. This anhydride may then be treated with an appropriateprimary or secondary amine to provide the desired amide. Finally, thecarboxylic acid may be treated with a typical peptide coupling reagentsuch as N,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide(DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC), followed by the appropriate amine of formula R⁵XNH. Apolymer-supported form of EDC has been described in Tetrahedron Letters,34(48), 7685 (1993), the disclosure of which is incorporated herein byreference, and is very useful for the preparation of the compounds ofthe present invention. It is appreciated that substituting anappropriate amine with an appropriate alcohol in the synthethic schemepresented above will provide the esters of the invention, e.g. analogsof I-a with a different ester R^(6′)O—.

The carboxylic acid may alternatively be converted into thecorresponding tert-butyl ester via treatment of the acid with an acidcatalyst, such as concentrated sulfuric acid, and the like, and withisobutylene in a suitable solvent, such as dioxane, and the like. Thereaction is preferably carried out under pressure in an appropriatevessel, such as a pressure bottle, and the like. Reaction times of about18 hours are not uncommon. The desired ester may be be isolated from theorganic layer after partitioning the reaction mixture between a suitableorganic solvent, such as ethyl acetate, and the like, and a basicaqueous layer, such as cold 1N sodium hydroxide, and the like.

It is appreciated that the transformation illustrated in SyntheticScheme VII may also be used to convert in an analogous fashion, thehalf-ester I where A is R⁶O— to the corresponding acid and subsequentlyinto derivatives I where A is XNH—, R⁵XN—, or a different R⁶O—. Finally,it is appreciated that the transformation in Synthetic Scheme VII mayalso be used to convert in an analogous fashion the esters of formulaII, where A is R⁶O—, to the corresponding acids, and subsequently intoderivatives of formula II, where A is XNH—, R⁵XN—, or a different R⁶O—.

Compounds of formulae I and II where R⁴ includes an ethenyl or ethynylspacer, such as for example, compounds I-c and I-d, respectively, may beconverted into the corresponding arylethyl derivatives, compounds I-e,via reduction, as illustrated for compounds of formula I in SyntheticScheme VIII. Conversion is accomplished by catalytic hydrogenation, andother like reductions, where the integer n and the groups R², R³, A, andA′ are as previously defined. The corresponding compounds of formula IImay also be converted from ethyne and ethene precursors in an analogousfashion. The moiety R depicted in Scheme VIII is chosen such that thesubstituent R—CC—, R—CHCH—, or R—CH₂CH₂— corresponds to the desired R⁴of formulae I or II as defined above.

Synthetic Scheme VIII

The hydrogenation of the triple or double bond proceeds readily over aprecious metal catalyst, such as palladium on carbon. The hydrogenationsolvent may consist of a lower alkanol, such as methanol or ethanol,tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethylacetate. The hydrogenation may be performed at an initial hydrogenpressure of about 20–80 p.s.i., preferably about 50–60 p.s.i., at atemperature of about 0–60° C., preferably within the range of fromambient temperature to about 40° C., for about 1 hour to about 3 days.

Alternatively, the ethynyl spacer of compound I-c may be selectivelyreduced to the ethenyl spacer of compound I-d using poisoned catalyts,such as Pd on BaSO₄, Lindlar's catalyst, and the like. It is appreciatedthat either the Z or E double bond geometry of compound I-d may beadvantageously obtained by the appropriate choice of reactionconditions. The analogous synthesis of compounds of formula II may beaccomplished by this process.

Compounds of formula I and II where R³ is phthalimido are convenientlytreated with hydrazine or a hydrazine derivative, for examplemethylhydrazine, to prepare the corresponding 2-(3-amino-4-substitutedazetidin-2-on-1-yl)alkanedioic acid derivatives xiii, as illustrated inSynthetic Scheme IX for compounds of formula I, where the integer n, andthe groups R², R⁴, R¹², A, and A′ are as previously defined. Thiscompound may then be treated with an appropriate alkylating or acylatingagent to prepare the corresponding amines or amides I-g, oralternatively intermediates xiii may be treated with an appropriateisocyanate to prepare the corresponding ureas I-h.

Synthetic Scheme IX

The ureas I-h are prepared by treating a solution of the appropriateamine xiii in a suitable solvent, such as chloroform or dichloromethane,with an appropriate isocyanate, R¹²NCO. If necessary, an excess of theisocyanate is employed to ensure complete reaction of the startingamine. The reactions are performed at about ambient temperature to about45° C., for from about three hours to about three days. Typically, theproduct may be isolated by washing the reaction with water andconcentrating the remaining organic components under reduced pressure.When an excess of isocyanate has been used, however, a polymer boundprimary or secondary amine, such as an aminomethylated polystyrene, maybe conveniently added to facilitate removal of the excess reagent.Isolation of products from reactions where a polymer bound reagent hasbeen used is greatly simplified, requiring only filtration of thereaction mixture and then concentration of the filtrate under reducedpressure.

The substituted amines and amides I-g are prepared by treating asolution of the appropriate amine xiii in a suitable solvent, such aschloroform or dichloromethane, with an appropriate acylating oralkylating agent, R¹²—C(O)Z or R¹²-Z, respectively. If necessary, anexcess of the acylating or alkylating agent is employed to ensurecomplete reaction of the starting amine. The reactions are performed atabout ambient temperature to about 45° C., for from about three hours toabout three days. Typically, the product may be isolated by washing thereaction with water and concentrating the remaining organic componentsunder reduced pressure. When an excess of the acylating or alkylatingagent has been used, however, a polymer bound primary or secondaryamine, such as an aminomethylated polystyrene, may be conveniently addedto facilitate removal of the excess reagent. Isolation of products fromreactions where a polymer bound reagent has been used is greatlysimplified, requiring only filtration of the reaction mixture and thenconcentration of the filtrate under reduced pressure. The analogoussynthesis of compounds of formula II may be accomplished by thisprocess.

The following preparations and examples further illustrate the synthesisof the compounds of this invention and are not intended to limit thescope of the invention in any way. Unless otherwise indicated, allreactions were performed at ambient temperature, and all evaporationswere performed in vacuo. All of the compounds described below werecharacterized by standard analytical techniques, including nuclearmagnetic resonance spectroscopy (¹H NMR) and mass spectral analysis(MS).

EXAMPLE 1 (4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride

A solution of 1.0 equivalent of (4(S)-phenyloxazolidin-2-on-3-yl)aceticacid (Evans, U.S. Pat. No. 4,665,171) and 1.3 equivalent of oxalylchloride in 200 mL dichloromethane was treated with a catalytic amountof anhydrous dimethylformamide (85 μL/milliequivalent of acetic acidderivative) resulting in vigorous gas evolution. After 45 minutes allgas evolution had ceased and the reaction mixture was concentrated underreduced pressure to provide the title compound as an off-white solidafter drying for 2 h under vacuum.

EXAMPLE 2 General Procedure for Amide Formation from an Activated EsterDerivative

N-Benzyloxycarbonyl-L-aspartic acid β-t-butyl esterα-(3-trifluoromethyl)benzylamide.

A solution of N-benzyloxycarbonyl-L-aspartic acid β-t-butyl esterα-N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in20 mL of dry tetrahydrofuran was treated with 0.68 mL (4.74 mmol) of3-(trifluoromethyl)benzyl amine. Upon completion (TLC, 60:40hexanes/ethyl acetate), the mixture was evaporated, and the resultingoil was partitioned between dichloromethane and a saturated aqueoussolution of sodium bicarbonate. The organic laer was evaporated to give2.23 g (quantitative yield) of the title compound as a white solid; ¹HNMR (CDCl₃) δ 1.39 (s, 9H), 2.61 (dd, J=6.5 Hz, J=17.2 Hz, 1H), 2.98(dd, J=3.7 Hz, J=17.0 Hz, 1H), 4.41 (dd, J=5.9 Hz, J=15.3 Hz, 1H),4.50–4.57 (m, 2H), 5.15 (s, 2H), 5.96–5.99 (m, 1H), 6.95 (s, 1H),7.29–7.34 (m, 5H), 7.39–7.43 (m, 2H), 7.48–7.52 (m, 2H).

Examples 3–5 were prepared according to the procedure of Example 2,except that N-benzyloxycarbonyl-L-aspartic acid β-t-butyl esterα-N-hydroxysuccinimide ester was replaced by the appropriate amino acidderivative, and 3-(trifluoromethyl)benzyl amine was replaced with theappropriate amine.

EXAMPLE 3 N-Benzyloxycarbonyl-L-aspartic acid β-t-butyl esterα-[4-(2-phenylethyl)]piperazinamide

N-benzyloxycarbonyl-L-aspartic acid β-t-butyl esterα-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and4-(phenylethyl)piperazine 2.27 mL (11.9 mmol) gave 5.89 g (quantitativeyield) of the title compound as an off-white oil; ¹H NMR (CDCl₃) δ 1.40(s, 9H), 2.45–2.80 (m, 10H), 3.50–3.80 (m, 4H), 4.87–4.91 (m, 1H), 5.08(s, 2H), 5.62–5.66 (m, 1H), 7.17–7.33 (m, 10H).

EXAMPLE 4 N-Benzyloxycarbonyl-L-glutamic acid γ-t-butyl esterα-(3-trifluoromethyl)benzylamide

N-benzyloxycarbonyl-L-glutamic acid β-t-butyl esterα-N-hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced ChemTech) and3-(trifluoromethyl)benzylamine) 1.63 mL (11.4 mmol) gave 5.41 g (98%) ofthe title compound as an off-white solid; ¹H NMR (CDCl₃) δ 1.40 (s, 9H),1.88–1.99 (m, 1H), 2.03–2.13 (m, 1H), 2.23–2.33 (m, 1H), 2.38–2.47 (m,1H), 4.19–4.25 (s, 1H), 4.46–4.48 (m, 2H), 5.05–5.08 (m, 2H), 5.67–5.72(m, 1H), 7.27–7.34 (m, 5H), 7.39–7.43 (m, 2H), 7.48–7.52 (m, 2H).

EXAMPLE 5 N-Benzyloxycarbonyl-L-glutamic acid γ-t-butyl esterα-[4-(2-phenylethyl)]piperazinamide

N-benzyloxycarbonyl-L-glutamic acid γ-t-butyl esterα-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and4-(phenylethyl)piperazine 2.19 mL (11.5 mmol) gave 5.87 g (quantitativeyield) of the title compound as an off-white oil; ¹H NMR (CDCl₃) δ 1.43(s, 9H); 1.64–1.73 (m, 1H); 1.93–2.01 (m, 1H); 2.23–2.40 (m, 2H);2.42–2.68 (m, 6H); 2.75–2.85 (m, 2H); 3.61–3.74 (m, 4H); 4.66–4.73 (m,1H); 5.03–5.12 (m, 2H); 5.69–5.72 (m, 1H); 7.16–7.34 (m, 10H).

EXAMPLE 5A N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serinet-Butyl ester

N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine (0.710 g, 1.70mmole) in dichloromethane (8 mL) was treated with t-butyl acetate (3 mL)and concentrated sulfuric acid (40 μL) in a sealed flask at 0° C. Uponcompletion (TLC), the reaction was quenched with of dichloromethane (10mL) and saturated aqueous potassium bicarbonate (15 mL). The organiclayer was washed with distilled water, and evaporated. The resultingresidue was purified by flash column chromatography (98:2dichloromethane/methanol) to yield the title compound as a colorless oil(0.292 g, 77%); ¹H NMR (CDCl₃) δ 1.44 (s, 9H); 3.68 (dd, J=2.9 Hz, J=9.3Hz, 1H); 3.87 (dd, J=2.9 Hz, J=9.3 Hz, 1H); 4.22 (t, J=7.1 Hz, 1H);4.30–4.60 (m, 5H); 5.64–5.67 (m, 1H); 7.25–7.39 (m, 9H); 7.58–7.61 (m,2H); 7.73–7.76 (m, 2H).

EXAMPLE 5B O-(Benzyl)-D-serine t-Butyl ester

Example 5A (0.620 g, 1.31 mmol) in dichloromethane (5 mL) was treatedwith tris(2-aminoethyl)amine (2.75 mL) for 5 h. The resulting mixturewas washed twice with a phosphate buffer (pH=5.5), once with saturatedaqueous potassium bicarbonate, and evaporated to give 0.329 g(quantitative yield) of the title compound as an off-white solid; ¹H NMR(CD₃OD) δ 1.44 (s, 9H); 3.48 (dd, J=J′=4.2 Hz, 1H); 3.61 (dd, J=4.0 Hz,J=9.2 Hz, 1H); 3.72 (dd, J=4.6 Hz, J=9.2 Hz, 1H); 4.47 (d, J=12.0 Hz,1H); 4.55 (d, J=12.0 Hz, 1H); 7.26–7.33 (m, 5H).

EXAMPLE 6 General Procedure for Amide Formation from a Carboxylic Acid

N-Benzyloxycarbonyl-D-aspartic acid β-t-butyl esterα-(3-trifluoromethyl)benzylamide.

A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acidβ-t-butyl ester monohydrate (Novabiochem) in 3–4 mL of dichloromethanewas treated by sequential addition of 0.46 mL (3.21 mmol) of3-(trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) of1-hydroxy-7-benzotriazole, and 0.62 g (3.23 mmol) of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After atleast 12 hours at ambient temperature or until complete as determined bythin layer chromatography (95:5 dichloromethane/methanol eluent), thereaction mixture was washed sequentially with a saturated aqueous sodiumbicarbonate solution and with distilled water. The organic layer wasevaporated to give 1.41 g (quantitative yield) of the title compound asan off-white solid; ¹H NMR (CDCl₃) δ 1.39 (s, 9H); 2.61 (dd, J=6.5 Hz,J=17.2 Hz, 1H); 2.98 (dd, J=4.2 Hz, J=17.2 Hz, 1H); 4.41 (dd, J=5.9 Hz,J=15.3 Hz, 1H); 4.50–4.57 (m, 2H); 5.10 (s, 2H); 5.96–6.01 (m, 1H);6.91–7.00 (m, 1H); 7.30–7.36 (m, 5H); 7.39–7.43 (m, 2H); 7.48–7.52 (m,2H).

Examples 7 and 7A–7E were prepared according to the procedure of Example6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butyl estermonohydrate was replaced by the appropriate amino acid derivative, and3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine.

EXAMPLE 7 N-Benzyloxycarbonyl-D-glutamic acid γ-t-butyl esterα-(3-trifluoromethyl)benzylamide

N-benzyloxycarbonyl-D-glutamic acid γ-t-butyl ester (1.14 g, 3.37 mmol)and 0.53 mL (3.70 mmol, Novabiochem) of 3-(trifluoromethyl)benzylaminegave 1.67 g (quantitative yield) of Example 7 as an off-white solid.

EXAMPLE 7A N-Benzyloxycarbonyl-L-glutamic acid α-t-butyl esterγ-(4-cyclohexyl)piperazinamide

N-benzyloxycarbonyl-L-glutamic acid α-t-butyl ester (1.36 g, 4.03 mmol)and 0.746 g (4.43 mmol) of 1-cyclohexylpiperazine gave 1.93 g (98%) ofExample 7A as an off-white solid; ¹H NMR (CDCl₃) δ 1.02–1.12 (m, 5H);1.43 (s, 9H), 1.60–1.64 (m, 1H); 1.80–1.93 (m, 5H); 2.18–2.52 (m, 8H);3.38–3.60 (m, 4H); 4.20–4.24 (m, 1H); 5.03–5.13 (m, 2H); 5.53–5.57 (m,1H); 7.28–7.34 (m, 5H).

EXAMPLE 7B N-Benzyloxycarbonyl-D-aspartic acid β-t-butyl esterα-(2-fluoro-3-trifluoromethyl)benzylamide

N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate(Novabiochem) (0.25 g, 0.73 mmol) and 0.12 mL of(2-fluoro-3-trifluoromethyl)benzylamine gave 0.365 g (quantitativeyield) of Example 7B as an off-white solid; ¹H NMR (CDCl₃) δ 1.38 (s,9H); 2.59 (dd, J=6.5 Hz, J=17.0 Hz, 1H); 2.95 (dd, J=4.3 Hz, J=17.0 Hz,1H); 4.46–4.56 (m, 3H); 5.11 (s, 2H); 5.94–5.96 (m, 1H); 7.15 (t, J=8.0Hz, 1H); 7.30–7.36 (m, 5H); 7.47–7.52 (m, 2H).

EXAMPLE 7C N-Benzyloxycarbonyl-D-aspartic acid β-t-butyl esterα-[(S)-α-methylbenzyl]amide

N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrateNovabiochem) (0.25 g, 0.73 mmol) and 0.094 mL of (S)-α-methylbenzylaminegave 0.281 g (90%) of Example 7C as an off-white solid; ¹H NMR (CDCl₃) δ1.41 (s, 9H); 1.44 (d, J=7.0 Hz, 3H); 2.61 (dd, J=7.0 Hz, J=17.0 Hz,1H); 2.93 (dd, J=4.0 Hz, J=17.5 Hz, 1H); 4.50–4.54 (m, 1H); 5.04–5.14(m, 3H); 5.94–5.96 (m, 1H); 6.76–6.80 (m, 1H); 7.21–7.37 (m, 10H).

EXAMPLE 7D N-Benzyloxycarbonyl-D-aspartic acid β-t-butyl esterα-[(R)-α-methylbenzyl]amide

N-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate(Novabiochem) (0.25 g, 0.73 mmol) and 0.094 mL of(R)-α-methylbenzylamine gave 0.281 g (90%) of Example 7D as an off-whitesolid; ¹H NMR (CDCl₃) δ 1.38 (s, 9H); 1.43 (d, J=6.9 Hz, 3H); 2.54 (dd,J=7.3 Hz, J=17.2 Hz, 1H); 2.87 (dd, J=4.1 Hz, J=17.3 Hz, 1H); 4.46–4.50(m, 1H); 4.99–5.15 (m, 3H); 5.92–5.96 (m, 1H); 6.78–6.82 (m, 1H);7.21–7.33 (m, 10H).

EXAMPLE 7E N-Benzyloxycarbonyl-D-aspartic acid γ-t-butyl esterα-[N-methyl-N-(3-trifluoromethylbenzyl)]amide

N-benzyloxycarbonyl-D-aspartic acid γ-t-butyl ester (0.303 g, 0.89 mmol,Novabiochem) and 0.168 g (0.89 mmol) ofN-methyl-N-(3-trifluoromethylbenzyl)amine gave 0.287 g (65%) of Example7E as an off-white solid; ¹H NMR (CDCl₃) δ 1.40 (s, 9H); 2.55 (dd, J=5.8Hz, J=15.8 Hz, 1H); 2.81 (dd, J=7.8 Hz, J=15.8 Hz, 1H); 3.10 (s, 3H);4.25 (d, J=15.0 Hz, 1H); 4.80 (d, J=15.5 Hz, 1H); 5.01–5.13 (m, 3H);5.52–5.55 (m, 1H); 7.25–7.52 (m, 10H).

EXAMPLE 8 General Procedure for Hydrogenation of a BenzyloxycarbonylAmine

L-aspartic acid β-t-butyl ester α-(3-trifluoromethyl)benzylamide.

A suspension of 2.23 g (4.64 mmol) of N-benzyloxycarbonyl-L-asparticacid β-t-butyl ester α-(3-trifluoromethyl)benzylamide and palladium (5%wt. on activated carbon, 0.642 g) in 30 mL of methanol was held under anatmosphere of hydrogen until complete conversion as determined by thinlayer chromatography (95:5 dichloromethane/methanol eluent). Thereaction was filtered to remove the palladium over carbon and thefiltrate was evaporated to give 1.52 g (96%) of the title compound as anoil; ¹H NMR (CDCl₃) δ 1.42 (s, 9H); 2.26 (brs, 2H); 2.63–2.71 (m, 1H);2.82–2.87 (m, 1H); 3.75–3.77 (m, 1H); 4.47–4.50 (m, 2H); 7.41–7.52 (m,4H); 7.90 (brs, 1H).

Examples 9–13 and 13A–13E were prepared according to the procedure ofExample 8, except that N-benzyloxycarbonyl-L-aspartic acid β-t-butylester α-(3-trifluoromethyl)benzylamide was replaced by the appropriateamino acid derivative.

EXAMPLE 9 L-aspartic acid β-t-butyl esterα-[4-(2-phenylethyl)]piperazinamide

N-benzyloxycarbonyl-L-aspartic acid β-t-butyl esterα-[4-(2-phenylethyl)]piperazinamide (5.89 g, 11.9 mmol) gave 4.24 g(98%) of Example 9 as an off-white oil; ¹H NMR (CDCl₃): δ 1.42 (s, 9H);2.61–2.95 (m, 10H); 3.60–3.90 (m, 4H); 4.35–4.45 (m, 1H); 7.17–7.29 (m,5H).

EXAMPLE 10 D-aspartic acid β-t-butyl esterα-(3-trifluoromethyl)benzylamide

N-benzyloxycarbonyl-D-aspartic acid β-t-butyl esterα-(3-trifluoromethyl)benzylamide (1.41 g, 2.93 mmol) gave 0.973 g (96%)of Example 10 as an off-white oil; ¹H NMR (CDCl₃): δ 1.42 (s, 9H); 2.21(brs, 2H); 2.67 (dd, J=7.1 Hz, J=16.8 Hz, 1H); 2.84 (dd, J=3.6 Hz,J=16.7 Hz, 1H); 3.73–3.77 (m, 1H); 4.47–4.50 (m, 2H); 7.41–7.52 (m, 4H);7.83–7.87 (m, 1H).

EXAMPLE 11 L-glutamic acid γ-t-butyl esterα-(3-trifluoromethyl)benzylamide

N-benzyloxycarbonyl-L-glutamic acid γ-t-butyl esterα-(3-trifluoromethyl)benzylamide (5.41 g, 10.9 mmol) gave 3.94 g(quantitative yield) of Example 11 as an off-white oil; ¹H NMR (CDCl₃):δ 1.41 (s, 9H); 1.73–1.89 (m, 3H); 2.05–2.16 (m, 1H); 2.32–2.38 (m, 2H);3.47 (dd, J=5.0 Hz, J=7.5 Hz, 1H); 4.47–4.49 (m, 2H); 7.36–7.54 (m, 4H);7.69–7.77 (m, 1H).

EXAMPLE 12 L-glutamic acid γ-t-butyl esterα-[4-(2-phenylethyl)]piperazinamide

N-benzyloxycarbonyl-L-glutamic acid γ-t-butyl esterα-[4-(2-phenylethyl)]piperazinamide (5.86 g, 11.50 mmol) gave 4.28 g(99%) of Example 12 as an off-white oil; ¹H NMR (CDCl₃) δ 1.39 (s, 9H);2.00–2.08 (m, 1H); 2.38–2.46 (m, 1H); 2.55–2.90 (m, 9H); 3.61–3.82 (m,4H); 4.48–4.56 (m, 1H); 7.17–7.26 (m, 5H).

EXAMPLE 13 D-glutamic acid γ-t-butyl esterα-(3-trifluoromethyl)benzylamide

N-benzyloxycarbonyl-D-glutamic acid γ-t-butyl esterα-(3-trifluoromethyl)benzylamide (1.667 g, 3.37 mmol) gave 1.15 g (94%)of Example 13 as an off-white oil; ¹H NMR (CDCl₃) δ 1.41 (s, 9H);1.80–2.20 (m, 4H); 2.31–2.40 (m, 2H); 3.51–3.59 (m, 1H); 4.47–4.49 (m,2H); 7.39–7.52 (m, 4H); 7.71–7.79 (m, 1H).

EXAMPLE 13A L-glutamic acid α-t-butyl esterγ-(4-cyclohexyl)piperazinamide

N-Benzyloxycarbonyl-L-glutamic acid α-t-butyl esterγ-(4-cyclohexyl)piperazinamide (1.93 g, 3.96 mmol) gave 1.30 g (93%) ofExample 13A as an off-white oil; ¹H NMR (CDCl₃) δ 1.02–1.25 (m, 5H);1.41 (s, 9H); 1.45–1.50 (m, 1H); 1.56–1.60 (m, 1H); 1.69–1.80 (m, 6H);3.30 (dd, J=4.8 Hz, J=8.5 Hz, 1H); 3.44 (t, J=9.9 Hz, 2H); 3.56 (t,J=9.9 Hz, 2H).

EXAMPLE 13B D-aspartic acid β-t-butyl esterα-(2-fluoro-3-trifluoromethyl)benzylamide

N-benzyloxycarbonyl-D-aspartic acid β-t-butyl esterα-(2-fluoro-3-trifluoromethyl)benzylamide (0.36 g, 0.72 mmol) gave 0.256g (92%) of Example 13B as an off-white oil; ¹H NMR (CDCl₃) δ 1.39 (s,9H); 2.50 (brs, 2H); 2.74 (dd, J=7.0 Hz, J=16.5 Hz, 1H); 2.86 (dd, J=4.8Hz, J=16.8 Hz, 1H); 3.89 (brs, 2H); 4.47–4.57 (m, 2H); 7.16 (t, J=7.8Hz, 1H); 7.48 (t, J=7.3 Hz, 1H); 7.56 (t, J=7.3 Hz, 1H); 7.97–8.02 (m,1H).

EXAMPLE 13C D-aspartic acid β-t-butyl ester α-[(S)-α-methyl]benzylamide

N-benzyloxycarbonyl-D-aspartic acid β-t-butyl esterα-[(S)-α-methylbenzyl]amide (0.275 g, 0.65 mmol) gave 0.17 g (90%) ofExample 13C as an off-white oil; ¹H NMR (CDCl₃) δ 1.40 (s, 9H); 1.47 (d,J=6.9 Hz, 3H); 1.98 (brs, 2H); 2.49 (dd, J=7.9 Hz, J=17.7 Hz, 1H); 2.83(dd, J=3.6 Hz, J=16.7 Hz, 1H); 3.69 (brs, 1H); 4.99–5.10 (m, 1H);7.19–7.33 (m, 5H); 7.65–7.68 (m, 1H).

EXAMPLE 13D D-aspartic acid β-t-butyl ester α-[(R)-α-methylbenzyl]amide

N-benzyloxycarbonyl-D-aspartic acid β-t-butyl esterα-[(R)-α-methylbenzyl]amide (0.273 g, 0.64 mmol) gave 0.187 g(quantitative yield) of Example 13D as an off-white oil; ¹H NMR (CDCl₃)δ 1.38 (s, 9H); 1.46 (d, J=6.9 Hz, 3H); 1.79 (brs, 2H); 2.51 (dd, J=7.8Hz, J=17.5 Hz, 1H); 2.87 (dd, J=3.6 Hz, J=16.9 Hz, 1H); 4.19 (brs, 1H);4.99–5.11 (m, 1H); 7.18–7.34 (m, 5H); 7.86–7.90 (m, 1H).

EXAMPLE 13E D-aspartic acid β-t-butyl esterα-[N-methyl-N-(3-trifluoromethylbenzyl)]amide

N-benzyloxycarbonyl-D-aspartic acid β-t-butyl esterα-[N-methyl-N-(3-trifluoromethylbenzyl)]amide (0.282 g, 0.57 mmol) gave0.195 g (95%) of Example 13E as an off-white oil.

EXAMPLE 14 General Procedure for Formation of a 2-Azetidinone from anImine and an Acetyl Chloride

Step 1: General Procedure for Formation of an Imine from an Amino AcidDerivative.

A solution of 1 equivalent of an α-amino acid ester or amide indichloromethane is treated sequentially with 1 equivalent of anappropriate aldehyde, and a dessicating agent, such as magnesium sulfateor silica gel, in the amount of about 2 grams of dessicating agent pergram of starting α-amino acid ester or amide. The reaction is stirred atambient temperature until all of the reactants are consumed as measuredby thin layer chromatography. The reactions are typically completewithin an hour. The reaction mixture is then filtered, the filter cakeis washed with dichloromethane, and the filtrate concentrated underreduced pressure to provide the desired imine that is used as is in thesubsequent step.

Step 2: General Procedure for the 2+2 Cycloaddition of an Imine and anAcetyl Chloride.

A dichloromethane solution of the imine (10 mL dichloromethane/1 gramimine) is cooled to 0° C. To this cooled solution is added 1.5equivalents of an appropriate amine, typically triethylamine, followedby the dropwise addition of a dichloromethane solution of 1.1equivalents of an appropriate acetyl chloride, such as that described inExample 1 (10 mL dichloromethane/1 gm appropriate acetyl chloride). Thereaction mixture is allowed to warm to ambient temperature over 1 h andis then quenched by the addition of a saturated aqueous solution ofammonium chloride. The resulting mixture is partitioned between waterand dichloromethane. The layers are separated and the organic layer iswashed successively with 1N hydrochloric acid, saturated aqueous sodiumbicarbonate, and saturated aqueous sodium chloride. The organic layer isdried over magnesium sulfate and concentrated under reduced pressure.The residue may be used directly for further reactions, or purified bychromatography or by crystallization from an appropriate solvent systemif desired.

EXAMPLE 15 tert-Butyl[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate

Using the procedure of Example 14, the imine prepared from 4.53 g (34.5mmol) glycine tert-butyl ester and cinnamaldehyde was combined with2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give5.5 g (30%) of Example 15 as colorless crystals (recrystallized,n-chlorobutane); mp 194–195° C.

EXAMPLE 16 General procedure for acylation of an(azetidin-2-on-1-yl)acetate

A solution of (azetidin-2-on-1-yl)acetate in tetrahydrofuran (0.22 M inazetidinone) is cooled to −78° C. and is with lithiumbis(trimethylsilyl)amide (2.2 equivalents). The resulting anion istreated with an appropriate acyl halide (1.1 equivalents). Upon completeconversion of the azetidinone, the reaction is quenched with saturatedaqueous ammonium chloride and partitioned between ethyl acetate andwater. The organic phase is washed sequentially with 1N hydrochloricacid, saturated aqueous sodium bicarbonate, and saturated aqueous sodiumchloride. The resulting organic layer is dried (magnesium sulfate) andevaporated. The residue is purified by silica gel chromatography with anappropriate eluent, such as 3:2 hexane/ethyl acetate.

EXAMPLE 17 2,2,2-Trichloroethyl2(RS)-(tert-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate

Using the procedure of Example 16, 9.0 g (20 mmol) of Example 15 wasacylated with 4.2 g (20 mmol) of trichloroethylchloroformate to give 7.0g (56%) of Example 17; mp 176–178° C.

EXAMPLE 182(RS)-(tert-Butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

A solution of 0.20 g (0.32 mmol) of Example 17 and 52 μL (0.36 mmol) of(3-trifluoromethylbenzyl)amine in THF was heated at reflux. Uponcomplete conversion (TLC), the solvent was evaporated and the residuewas recrystallized (chloroform/hexane) to give 0.17 g (82%) of Example18 as a white solid; mp 182–184° C.

Examples 19–25 and 25A–25H were prepared according to the procedure ofExample 14, where the appropriate amino acid derivative and aldehydewere used in Step 1, and the appropriate acetyl chloride was used inStep 2.

EXAMPLE 19

2(S)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

The imine prepared from 1.52 g (4.39 mmol) of L-aspartic acid β-t-butylester α-(3-trifluoromethyl)benzylamide and cinnamaldehyde was combinedwith 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) togive 2.94 g of an orange-brown oil that gave, after flash columnchromatography purification (70:30 hexanes/ethyl acetate), 2.06 g (70%)of Example 19 as a white solid; ¹H NMR (CDCl₃) δ 1.39 (s, 9H); 2.46 (dd,J=11.1 Hz, J=16.3 Hz, 1H); 3.18 (dd, J=3.8 Hz, J=16.4 Hz, 1H); 4.12–4.17(m, 1H); 4.26 (d, J=5.0 Hz, 1H); 4.45 (dd, J=6.0 Hz, J=14.9 Hz, 1H);4.54 (dd, J=5.3 Hz, J=9.8 Hz, 1H); 4.58–4.66 (m, 3H); 4.69–4.75 (m, 1H);4.81 (dd, J=3.8 Hz, J=11.1 Hz, 1H); 6.25 (dd, J=9.6 Hz, J=15.8 Hz, 1H);6.70 (d, J=15.8 Hz, 1H); 7.14–7.17 (m, 2H); 7.28–7.46 (m, 11H); 7.62 (s,1H); 8.27–8.32 (m, 1H).

EXAMPLE 202(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

The imine prepared from 3.94 g (10.93 mmol) of L-glutamic acid γ-t-butylester α-(3-trifluoromethyl)benzylamide and cinnamaldehyde was combinedwith 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) togive 5.53 g (75%) of Example 20 after flash column chromatographypurification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.36 (s,9H); 1.85–1.96 (m, 1H); 2.18–2.49 (m, 3H); 4.14–4.19 (m, 1H); 4.30 (d,J=4.9 Hz, 2H); 4.44 (dd, J=6.1 Hz, J=14.9 Hz, 1H); 4.56–4.67 (m, 4H);4.71–4.75 (m, 1H); 6.26 (dd, J=9.6 Hz, J=15.8 Hz, 1H); 6.71 (d, J=15.8Hz, 1H); 7.16–7.18 (m, 2H); 7.27–7.49 (m, 11H); 7.60 (s, 1H); 8.08–8.12(m, 1H).

EXAMPLE 212(S)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-[4-(2-phenylethyl)]piperazinamide

The imine prepared from 4.20 g (11.6 mmol) of L-aspartic acid β-t-butylester α-[4-(2-phenylethyl)]piperazinamide and cinnamaldehyde wascombined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride(Example 1) to give 4.37 g (55%) of Example 21 after flash columnchromatography purification (50:50 hexanes/ethyl acetate); ¹H NMR(CDCl₃) δ 1.34 (s, 9H); 2.26–2.32 (m, 1H); 2.46–2.63 (m, 4H); 2.75–2.89(m, 4H); 3.24–3.32 (m, 1H); 3.49–3.76 (m, 3H); 4.07–4.13 (m, 1H); 4.30(d, J=4.6 Hz, 1H); 4.22–4.48 (m, 1H); 4.55–4.61 (m, 1H); 4.69–4.75 (m,1H); 5.04–5.09 (m, 1H); 6.15 (dd, J=9.3 Hz, J=15.9 Hz, 1H); 6.63 (d,J=15.8 Hz, 1H); 7.18–7.42 (m, 15H).

EXAMPLE 222(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-[4-(2-phenylethyl)]piperazinamide

The imine prepared from 2.54 g (6.75 mmol) of L-glutamic acid γ-t-butylester α-[4-(2-phenylethyl)]piperazinamide and cinnamaldehyde wascombined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride(Example 1) to give 3.55 g (76%) of Example 22 after flash columnchromatography purification (50:50 hexanes/ethyl acetate); ¹H NMR(CDCl₃) δ 1.32 (s, 9H); 1.96–2.07 (m, 1H); 2.15–2.44 (m, 6H); 2.54–2.62(m, 2H); 2.69–2.81 (m, 3H); 3.28–3.34 (m, 1H); 3.59–3.68 (m, 1H);4.08–4.13 (m, 1H); 4.33–4.44 (m, 2H); 4.48–4.60 (m, 2H); 4.67–4.77 (m,1H); 6.14 (dd, J=8.9 Hz, J=16.0 Hz, 1H); 6.62 (d, J=16.0 Hz, 1H);7.16–7.42 (m, 15H).

EXAMPLE 232(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

The imine prepared from 0.973 g (2.81 mmol) of D-aspartic acid β-t-butylester α-(3-trifluoromethyl)benzylamide and cinnamaldehyde was combinedwith 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) togive 1.53 g (82%) of Example 23 after flash column chromatographypurification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.37 (s,9H); 3.10 (dd, J=3.7 Hz, J=17.8 Hz, 1H); 3.20 (dd, J=10.7 Hz, J=17.8 Hz,1H); 4.02 (dd, J=3.6 Hz, J=10.6 Hz, 1H); 4.11–4.17 (m, 1H); 4.24 (d,J=4.9 Hz, 1H); 4.46 (dd, J=5.8 Hz, J=15.1 Hz, 1H); 4.58–4.67 (m, 3H);4.70–4.76 (m, 1H); 6.27 (dd, J=9.5 Hz, J=15.8 Hz, 1H); 6.79 (d, J=15.8Hz, 1H); 7.25–7.50 (m, 13H); 7.63 (s, 1H); 8.50–8.54 (m, 1H).

EXAMPLE 242(R)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

The imine prepared from 1.15 g (3.20 mmol) of D-glutamic acid γ-t-butylester α-(3-trifluoromethyl)benzylamide and cinnamaldehyde was combinedwith 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) togive 1.84 g (85%) of Example 24 after flash column chromatographypurification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.37 (s,9H); 2.23–2.39 (m, 4H); 3.71–3.75 (m, 1H); 4.13–4.18 (m, 1H); 4.31 (d,J=4.9 Hz, 1H); 4.44–4.51 (m, 2H); 4.56–4.68 (m, 2H); 4.71–4.76 (m, 1H);6.26 (dd, J=9.5 Hz, J=15.8 Hz, 1H); 6.71 (d, J=15.8 Hz, 1H); 7.25–7.52(m, 13H); 7.63 (s, 1H); 8.25–8.30 (m, 1H).

Example 252(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(4-cyclohexyl)piperazinamide

The imine prepared from 2.58 g (5.94 mmol) of L-glutamic acid γ-t-butylester α-(4-cyclohexyl)piperazinamide and cinnamaldehyde was combinedwith 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) togive 3.27 g (94%) of Example 25 after flash column chromatographypurification (95:5 dichloromethane/methanol); ¹H NMR (CDCl₃) δ 1.32 (s,9H); 1.10–1.18 (m, 1H); 1.20–1.31 (m, 2H); 1.38–1.45 (m, 2H); 1.61–1.66(m, 1H); 1.84–1.89 (m, 2H); 1.95–2.01 (m, 1H); 2.04–2.14 (m, 3H);2.20–2.24 (m, 1H); 2.29–2.35 (m, 1H); 2.85–2.92 (m, 1H); 3.24–3.32 (m,1H); 3.36–3.45 (m, 2H); 3.80–3.86 (m, 1H); 4.08 (t, J=8.3 Hz, 1H); 4.27(d, J=5.0 Hz, 1H); 4.31–4.55 (m, 4H); 4.71 (t, J=8.3 Hz, 1H); 4.83–4.90(m, 1H); 6.18 (dd, J=9.1 Hz, J=15.9 Hz, 1H); 6.67 (d, J=15.9 Hz, 1H);7.25–7.44 (m, 10H); 8.22 (brs, 1H).

EXAMPLE 25A tert-Butyl2(S)-(2-(4-cyclohexylpiperazin-1-ylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate

The imine prepared from 1.282 g (3.63 mmol) of L-glutamic acid α-t-butylester γ-(4-cyclohexyl)piperazinamide and cinnamaldehyde was combinedwith 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) togive 1.946 g (80%) of Example 25A after flash column chromatographypurification (50:50 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.15–1.26(m, 6H); 1.39 (s, 9H); 1.55–1.64 (m, 2H); 1.77–1.83 (m, 3H); 2.22–2.35(m, 2H); 2.40–2.50 (m, 6H); 2.75–2.79 (m, 1H); 3.43–3.48 (m, 1H);3.56–3.60 (m, 2H); 3.75–3.79 (m, 1H); 4.10 (t, J=8.3 Hz, 1H); 4.31–4.35(m, 2H); 4.58 (t, J=8.8 Hz, 1H); 4.73 (t, J=8.4 Hz, 1H); 6.17 (dd, J=8.6Hz, J=16.0 Hz, 1H); 6.65 (d, J=16.0 Hz, 1H); 7.27–7.42 (m, 10H).

EXAMPLE 25B2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(2-fluoro-3-trifluoromethylbenzyl)amide

The imine prepared from 0.256 g (0.70 mmol) of D-aspartic acid β-t-butylester α-(2-fluoro-3-trifluoromethyl)benzylamide and cinnamaldehyde wascombined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride(Example 1) to give 0.287 g (60%) of Example 25B after flash columnchromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR(CDCl₃) δ 1.38 (s, 9H); 3.12 (dd, J=4.0 Hz, J=17.8 Hz, 1H); 3.20 (dd,J=10.4 Hz, J=17.8 Hz, 1H); 4.05 (dd, J=3.9 Hz, J=10.4 Hz, 1H); 4.14 (dd,J=J′=8.2 Hz, 1H); 4.25 (d, J=4.9 Hz, 1H); 4.59–4.67 (m, 4H); 4.74 (t,J=8.3 Hz, 1H); 6.36 (dd, J=9.6 Hz, J=15.8 Hz, 1H); 6.83 (d, J=15.8 Hz,1H); 7.02–7.07 (m, 1H); 7.28–7.55 (m, 12H); 8.44–8.48 (m, 1H).

EXAMPLE 25C2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-[(S)-α-methylbenzyl]amide

The imine prepared from 0.167 g (0.57 mmol) of D-aspartic acid β-t-butylester [(S)-α-methylbenzyl]amide and cinnamaldehyde was combined with2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give0.219 g (63%) of Example 25C after flash column chromatographypurification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.35 (s,9H); 1.56 (d, J=7.0 Hz, 3H); 2.97 (dd, J=3.5 Hz, J=18.0 Hz, 1H); 3.15(dd, J=11.0 Hz, J=17.5 Hz, 1H); 4.01 (dd, J=3.0 Hz, J=11.0 Hz, 1H); 4.14(t, J=8.5 Hz, 1H); 4.24 (d, J=5.0 Hz, 1H); 4.57 (dd, J=5.0 Hz, J=9.5 Hz,1H); 4.64 (t, J=8.8 Hz, 1H); 5.07 (t, J=8.5 Hz, 1H); 5.03–5.09 (m, 1H);6.43 (dd, J=9.5 Hz, J=16.0 Hz, 1H); 6.83 (d, J=16.0 Hz, 1H); 7.16–7.20(m, 1H); 7.27–7.49 (m, 14H); 8.07–8.10 (m, 1H).

EXAMPLE 25D2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-[(R)-α-methylbenzyl]amide

The imine prepared from 0.187 g (0.46 mmol) of D-aspartic acid β-t-butylester [(R)-α-methylbenzyl]amide and cinnamaldehyde was combined with2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give0.25 g (64%) of Example 25D after flash column chromatographypurification (70:30 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.36 (s,9H); 1.59 (d, J=7.1 Hz, 3H); 3.10 (dd, J=3.5 Hz, J=17.8 Hz, 1H); 3.22(dd, J=10.9 Hz, J=17.8 Hz, 1H); 3.93 (dd, J=3.5 Hz, J=10.8 Hz, 1H); 4.14(t, J=8.1 Hz, 1H); 4.24 (d, J=5.0 Hz, 1H); 4.58 (dd, J=5.0 Hz, J=9.5 Hz,1H); 4.65 (t, J=8.7 Hz, 1H); 4.74 (t, J=8.2 Hz, 1H); 5.06–5.14 (m, 1H);6.32 (dd, J=9.5 Hz, J=15.8 Hz, 1H); 6.74 (d, J=15.8 Hz, 1H); 7.19–7.43(m, 15H); 8.15–8.18 (m, 1H).

EXAMPLE 25E2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-methyl-N-(3-trifluoromethylbenzyl)amide

The imine prepared from 0.195 g (0.41 mmol) of D-aspartic acid β-t-butylester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide and cinnamaldehydewas combined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride(Example 1) to give 0.253 g (69%) of Example 25E after flash columnchromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR(CDCl₃) δ 1.36 (s, 9H); 2.53 (dd, J=4.0 Hz, J=17.0 Hz, 1H); 3.06 (dd,J=10.8 Hz, J=16.8 Hz, 1H); 3.13 (s, 3H); 4.12 (dd, J=8.0 Hz, J=9.0 Hz,1H); 4.26 (d, J=5.0 Hz, 1H); 4.38 (d, J=15.0 Hz, 1H); 4.46 (dd, J=5.0Hz, J=9.5 Hz, 1H); 4.56 (t, J=6.8 Hz, 1H); 4.70–4.79 (m, 2H); 5.27 (dd,J=4.0 Hz, J=11.0 Hz, 1H); 6.22 (dd, J=9.3 Hz, J=15.8 Hz, 1H); 6.73 (d,J=15.8 Hz, 1H); 7.33–7.45 (m, 14H).

EXAMPLE 25F2(S)-(tert-Butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-chlorostyr-2-yl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

The imine prepared from 1.62 g (4.44 mmol) of L-glutamic acid γ-t-butylester α-(3-trifluoromethyl)benzylamide and α-chlorocinnamaldehyde wascombined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride(Example 1) to give 0.708 g (22%) of Example 25F after flash columnchromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR(CDCl₃) δ 1.35 (s, 9H); 1.68 (brs, 1H); 2.19–2.35 (m, 2H); 2.40–2.61 (m,2H); 4.13 (dd, J=7.5 Hz, J=9.0 Hz, 1H); 4.22 (t, J=7.0 Hz, 1H); 4.34 (d,J=4.5 Hz, 1H); 4.45 (dd, J=5.5 Hz, J=15.0 Hz, 1H); 4.51–4.60 (m, 3H);4.89 (dd, J=7.5 Hz, J=8.5 Hz, 1H); 6.89 (s, 1H); 7.28–7.54 (m, 14H).

EXAMPLE 25G2(R)-(tert-Butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2′-methoxystyr-2-yl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

The imine prepared from 0.34 g (0.98 mmol) of D-aspartic acid β-t-butylester α-(3-trifluoromethylbenzyl)amide and 2′-methoxycinnamaldehyde wascombined with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride(Example 1) to give 0.402 g (59%) of Example 25G after flash columnchromatography purification (70:30 hexanes/ethyl acetate); ¹H NMR(CDCl₃) δ 1.35 (s, 9H); 1.68 (brs, 1H); 2.19–2.35 (m, 2H); 2.40–2.61 (m,2H); 4.13 (dd, J=7.5 Hz, J=9.0 Hz, 1H); 4.22 (t, J=7.0 Hz, 1H); 4.34 (d,J=4.5 Hz, 1H); 4.45 (dd, J=5.5 Hz, J=15.0 Hz, 1H); 4.51–4.60 (m, 3H);4.89 (dd, J=7.5 Hz, J=8.5 Hz, 1H); 6.89 (s, 1H); 7.28–7.54 (m, 14H).

EXAMPLE 25H tert-Butyl(2R)-(Benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate

The imine prepared from 0.329 g (1.31 mmol) of O-(benzyl)-D-serinet-butyl ester and cinnamaldehyde was combined with2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give0.543 g (73%) of Example 25H after flash column chromatographypurification (90:10 hexanes/ethyl acetate); ¹H NMR (CDCl₃) δ 1.39 (s,9H); 3.56 (dd, J=2.7 Hz, J=9.5 Hz, 1H); 3.82 (dd, J=4.8 Hz, J=9.5 Hz,1H); 4.11 (t, J=8.3 Hz, 1H); 4.21–4.29 (m, 2H); 4.50–4.58 (m, 3H);4.71–4.78 (m, 2H); 6.19 (dd, J=9.1 Hz, J=16.0 Hz, 1H); 6.49 (d, J=16.0Hz, 1H); 7.07–7.11 (m, 1H); 7.19–7.40 (m, 14H).

EXAMPLE 26 General Procedure for Hydrolysis of a Tert-Butyl Ester

A solution of tert-butyl ester derivative in formic acid, typically 1 gin 10 mL, is stirred at ambient temperature until no more ester isdetected by thin layer chromatography (dichloromethane 95%/methanol 5%),a typical reaction time being around 3 hours. The formic acid isevaporated under reduced pressure; the resulting solid residue ispartitioned between dichloromethane and saturated aqueous sodiumbicarbonate. The organic layer is evaporated to give an off-white solidthat may be used directly for further reactions, or recrystallized froman appropriate solvent system if desired.

Examples 27–34 and 34A–34H were prepared from the appropriate tert-butylester according to the procedure used in Example 26.

EXAMPLE 272(R,S)-(Carboxy)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 18 (0.30 g, 0.46 mmol) was hydrolyzed to give 0.27 g(quantitative yield) of Example 27 as an off-white solid; ¹H NMR (CDCl₃)δ 4.17–5.28 (m, 9H); 6.21–6.29 (m, 1H), 6.68–6.82 (m, 1H); 7.05–7.75 (m,13H); 9.12–9.18 (m, 1H).

EXAMPLE 282(S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 19 (1.72 g, 2.59 mmol) was hydrolyzed to give 1.57 g(quantitative yield) of Example 28 as an off-white solid; ¹H NMR (CDCl₃)δ 2.61 (dd, J=9.3 Hz, J=16.6 Hz, 1H); 3.09–3.14 (m, 1H); 4.10–4.13 (m,1H); 4.30 (d, J=4.5 Hz, 1H); 4.39–4.85 (m, 6H); 6.20 (dd, J=9.6 Hz,J=15.7 Hz, 1H); 6.69 (d, J=15.8 Hz, 1H); 7.12–7.15 (m, 2H); 7.26–7.50(m, 11H); 7.61 (s, 1H); 8.41–8.45 (m, 1H).

EXAMPLE 292(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 20 (4.97 g, 7.34 mmol) was hydrolyzed to give 4.43 g (97%) ofExample 29 as an off-white solid; ¹H NMR (CDCl₃) δ 1.92–2.03 (m, 1H);2.37–2.51 (m, 3H); 4.13–4.19 (m, 1H); 3.32 (d, J=4.9 Hz, 1H); 4.35–4.39(m, 1H); 4.44 (dd, J=5.9 Hz, J=14.9 Hz, 1H); 4.50–4.57 (m, 2H);4.61–4.67 (m, 1H); 4.70–4.76 (m, 1H); 6.24 (dd, J=9.6 Hz, J=15.8 Hz,1H); 6.70 (d, J=15.8 Hz, 1H); 7.18–7.47 (m, 14H).

EXAMPLE 302(S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-[4-(2-phenylethyl)]piperazinamide

Example 21 (1.88 g, 2.78 mmol) was hydrolyzed to give 1.02 g (60%) ofExample 30 as an off-white solid; ¹H NMR (CDCl₃) δ 2.63 (dd, J=6.0 Hz,J=16.5 Hz, 1H); 2.75–2.85 (m, 1H); 3.00 (dd, J=8.2 Hz, J=16.6 Hz, 1H);3.13–3.26 (m, 4H); 3.37–3.56 (m, 4H); 3.86–4.00 (m, 1H); 4.05–4.11 (m,1H); 4.24 (d, J=5.0 Hz, 1H); 4.46–4.66 (m, 1H); 4.65–4.70 (m, 1H);5.10–5.15 (m, 1H); 6.14 (dd, J=9.3 Hz, J=15.9 Hz, 1H); 6.71 (d, J=15.9Hz, 1H); 7.22–7.41 (m, 15H); 12.02 (s, 1H).

EXAMPLE 312(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-[4-(2-phenylethyl)]piperazinamide

Example 22 (0.383 g, 0.55 mmol) was hydrolyzed to give 0.352 g(quantitative yield) of Example 31 as an off-white solid; ¹H NMR (CDCl₃)δ 1.93–2.01 (m, 1H); 2.07–2.36 (m, 6H); 2.82–2.90 (m, 1H); 3.00–3.20 (m,4H); 3.36–3.54 (m, 4H); 3.74–3.82 (m, 1H); 4.06–4.11 (m, 1H); 4.29 (d,J=4.9 Hz, 1H); 4.33–4.46 (m, 2H); 4.50–4.58 (m, 2H); 4.67–4.72 (m, 1H);4.95–5.00 (m, 1H); 6.18 (dd, J=9.2 Hz, J=16.0 Hz, 1H); 6.67 (d, J=15.9Hz, 1H); 7.19–7.42 (m, 15H); 8.80 (brs, 1H).

EXAMPLE 322(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 23 (1.51 g, 2.27 mmol) was hydrolyzed to give 1.38 g(quantitative yield) of Example 32 as an off-white solid.

EXAMPLE 332(R)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 24 (0.604 g, 0.89 mmol) was hydrolyzed to give 0.554 g(quantitative yield) of Example 33 as an off-white solid.

EXAMPLE 342(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(4-cyclohexyl)piperazinamide

Example 25 (0.537 g, 0.80 mmol) was hydrolyzed to give 0.492 g(quantitative yield) of Example 34 as an off-white solid; ¹H NMR (CDCl₃)δ 1.09–1.17 (m, 1H); 1.22–1.33 (m, 2H); 1.40–1.47 (m, 2H); 1.63–1.67 (m,1H); 1.85–1.90 (m, 2H); 1.95–2.00 (m, 1H); 2.05–2.15 (m, 3H); 2.20–2.24(m, 1H); 2.30–2.36 (m, 1H); 2.85–2.93 (m, 1H); 3.25–3.33 (m, 1H);3.36–3.46 (m, 2H); 3.81–3.87 (m, 1H); 4.08 (t, J=8.3 Hz, 1H); 4.28 (d,J=5.0 Hz, 1H); 4.33–4.56 (m, 4H); 4.70 (t, J=8.3 Hz, 1H); 4.83–4.91 (m,1H); 6.17 (dd, J=9.1 Hz, J=15.9 Hz, 1H); 6.67 (d, J=15.9 Hz, 1H);7.25–7.44 (m, 10H); 8.22 (brs, 1H).

EXAMPLE 34A2(S)-(2-(4-Cyclohexylpiperazin-1-ylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid

Example 25A (0.787 g, 1.28 mmol) was hydrolyzed to give 0.665 g (92%) ofExample 34A as an off-white solid; ¹H NMR (CDCl₃) δ 1.05–1.13 (m, 1H);1.20–1.40 (m, 5H); 1.60–1.64 (m, 1H); 1.79–1.83 (m, 2H); 2.00–2.05 (m,2H); 2.22–2.44 (m, 3H); 2.67–2.71 (m, 1H); 2.93–3.01 (m, 4H); 3.14–3.18(m, 1H); 3.38–3.42 (m, 1H); 3.48–3.52 (m, 1H); 3.64–3.69 (m, 1H);4.06–4.14 (m, 2H); 4.34–4.43 (m, 2H); 4.56 (t, J=8.8 Hz, 1H); 4.73 (t,J=8.4 Hz, 1H); 6.15 (dd, J=9.1 Hz, J=16.0 Hz, 1H); 6.65 (d, J=16.0 Hz,1H); 7.25–7.42 (m, 10H).

EXAMPLE 34B2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(2-fluoro-3-trifluoromethylbenzyl)carboxamide

Example 25B (0.26 g, 0.38 mmol) was hydrolyzed to give 0.238 g(quantitative yield) of Example 34B as an off-white solid; ¹H NMR(CDCl₃) δ 3.27 (d, J=7.2 Hz, 1H); 4.06 (t, J=7.2 Hz, 1H); 4.15 (t, J=8.1Hz, 1H); 4.27 (d, J=4.8 Hz, 1H); 4.56–4.76 (m, 5H); 6.34 (dd, J=9.5 Hz,J=15.7 Hz, 1H); 6.80 (d, J=15.7 Hz, 1H); 7.06 (t, J=7.7 Hz, 1H);7.31–7.54 (m, 12H); 8.58 (t, J=5.9 Hz, 1H).

EXAMPLE 34C2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-[(S)-α-methylbenzyl]amide

Example 25C (0.215 g, 0.35 mmol) was hydrolyzed to give 0.195 g(quantitative yield) of Example 34C as an off-white solid; ¹H NMR(CDCl₃) δ 1.56 (d, J=7.0 Hz, 1H); 3.10 (dd, J=4.5 Hz, J=17.9 Hz, 1H);3.18 (dd, J=9.8 Hz, J=17.9 Hz, 1H); 4.00 (dd, J=4.5 Hz, J=9.7 Hz, 1H);4.14 (t, J=8.2 Hz, 1H); 4.26 (d, J=4.7 Hz, 1H); 5.02–5.09 (m, 1H); 6.41(dd, J=9.4 Hz, J=15.8 Hz, 1H); 6.78 (d, J=15.8 Hz, 1H); 7.18 (t, J=7.3Hz, 1H); 7.26–7.43 (m, 12H); 8.29 (d, J=8.2 Hz, 1H).

EXAMPLE 34D2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-[(R)-α-methylbenzyl]amide

Example 25D (0.22 g, 0.35 mmol) was hydrolyzed to give 0.20 g(quantitative yield) of Example 34D as an off-white solid; ¹H NMR(CDCl₃) δ 1.59 (d, J=7.0 Hz, 1H); 3.25 (d, J=7.0 Hz, 2H); 3.92 (t, J=7.3Hz, 1H); 4.15 (t, J=8.3 Hz, 1H); 4.26 (d, J=5.0 Hz, 1H); 4.52 (dd, J=4.8Hz, J=9.3 Hz, 1H); 4.65 (t, J=8.8 Hz, 1H); 4.72 (t, J=8.3 Hz, 1H);5.07–5.28 (m, 1H); 6.29 (dd, J=9.5 Hz, J=15.6 Hz, 1H); 6.71 d, J=16.0Hz, 1H); 7.20–7.43 (m, 13H); 8.31 (d, J=8.0 Hz, 1H).

EXAMPLE 34E2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-methyl-N-(3-trifluoromethylbenzyl)amide

Example 25E (0.253 g, 0.37 mmol) was hydrolyzed to give 0.232 g(quantitative yield) of Example 34E as an off-white solid; ¹H NMR(CDCl₃) δ 3.07–3.15 (m, 4H); 4.13 (t, J=8.2 Hz, 1H); 4.30 (d, J=4.9 Hz,1H); 4.46–4.78 (m, 5H); 5.23 (dd, J=4.6 Hz, J=9.7 Hz, 1H); 6.20 (dd,J=9.4 Hz, J=15.9 Hz, 1H); 6.73 (d, J=15.9 Hz, 1H); 7.25–7.43 (m, 15H).

EXAMPLE 34F2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-chlorostyr-2-yl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 25F (0.707 g, 0.99 mmol) was hydrolyzed to give 0.648 g (99%) ofExample 34F as an off-white solid; ¹H NMR (CDCl₃) δ 2.22–2.28 (m, 2H);2.49–2.64 (m, 2H); 4.09 (t, J=8.0 Hz, 1H); 4.25–4.62 (m, 6H); 4.87 (t,J=8.0 Hz, 1H); 6.88 (s, 1H); 7.25–7.66 (m, 15H).

EXAMPLE 34G2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2′-methoxystyr-2-yl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 25G (0.268 g, 0.39 mmol) was hydrolyzed to give 0.242 g (98%) ofExample 34G as an off-white solid; ¹H NMR (CDCl₃) δ 3.26 (d, J=7.1 Hz,1H); 3.79 (s, 3H); 4.14 (t, J=8.2 Hz, 1H); 4.25 (d, J=4.5 Hz, 1H); 4.51(dd, J=5.9 Hz, J=15.5 Hz, 1H); 4.53–4.66 (m, 4H); 6.36 (dd, J=9.4 Hz,J=15.8 Hz, 1H); 8.88 (t, J=8.2 Hz, 1H); 6.70 (d, J=15.8 Hz, 1H); 7.18(d, J=6.5 Hz, 1H); 7.25–7.48 (m, 10H); 7.48 (s, 1H); 8.66–8.69 (m, 1H).

EXAMPLE 34H(2R)-(Benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid

Example 25H (0.16 g, 0.28 mmol) was hydrolyzed to give 0.144 g(quantitative yield) of Example 34H as an off-white solid; ¹H NMR(CDCl₃) δ 3.65 (dd, J=4.0 Hz, J=9.5 Hz, 1H); 3.82 (dd, J=5.5 Hz, J=9.5Hz, 1H); 4.11 (dd, J=7.8 Hz, J=8.8 Hz, 1H); 4.33 (s, 2H); 4.50 (d, J=5.0Hz, 1H); 4.57 (t, J=9.0 Hz, 1H); 4.67 (dd, J=4.0 Hz, J=5.0 Hz, 1H); 4.69(dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.75 (t, J=8.0 Hz, 1H); 6.17 (dd, J=9.3Hz, J=15.8 Hz, 1H); 6.55 (d, J=16.0 Hz, 1H); 7.09–7.12 (m, 2H);7.19–7.42 (m, 13H).

EXAMPLE 352(S)-[4-(2-phenylethyl)piperazin-1-yl-carbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Using the procedure of Example 6, except thatN-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate wasreplaced with the carboxylic acid of Example 29 and3-(trifluoromethyl)benzyl amine was replaced with4-(2-phenylethyl)piperazine, the title compound was prepared; ¹H NMR(CDCl₃) δ 2.21–2.23 (m, 1H); 2.25–2.45 (m, 6H); 2.52–2.63 (m, 3H);2.72–2.82 (m, 2H); 3.42–3.48 (m, 2H); 3.52–3.58 (m, 1H); 4.13–4.18 (m,1H); 4.26 (dd, J=5.1 Hz, J=8.3 Hz, 1H); 4.29 (d, J=5.0 Hz, 1H); 4.44(dd, J=6.0 Hz, J=15.0 Hz, 1H); 4.54 (dd, J=6.2 Hz, J=14.9 Hz, 1H);4.61–4.68 (m, 2H); 4.70–4.75 (m, 1H); 6.27 (dd, J=9.6 Hz, J=15.8 Hz,1H); 6.73 (d, J=15.8 Hz, 1H); 7.16–7.60 (m, 19H); 8.07–8.12 (m, 1H);FAB⁺ (M+H)⁺/z 794; Elemental Analysis calculated for C₄₅H₄₆F₃N₅O₅: C,68.08; H, 5.84; N, 8.82; found: C, 67.94; H, 5.90; N, 8.64.

Examples 36–42 and 42A, shown in Table 6, were prepared using theprocedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acidβ-t-butyl ester monohydrate was replaced with Example 27, and3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine;all listed Examples exhibited an ¹H NMR spectrum consistent with theassigned structure.

TABLE 6

Example A′ 36 2-(piperidin-1-yl)ethylamino 374-(piperidin-1-yl)piperidin-1-yl 38 4-(2-phenylethyl)piperazin-1-yl 391-benzylpiperidin-4-ylamino 40 4-butylpiperazin-1-yl 414-isopropylpiperazin-1-yl 42 4-cyclohexylpiperazin-1-yl   42A4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl

Examples 43–86 and 86A, shown in Table 7, were prepared using theprocedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acidβ-t-butyl ester monohydrate was replaced with Example 28, and3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine;all listed Examples exhibited an ¹H NMR spectrum signed structure.

TABLE 7

Example A′ 43 2-(piperidin-1-yl)ethylamino 444-(piperidin-1-yl)piperidin-1-yl 45 4-(phenylethyl)piperazin-1-yl 46fur-2-ylmethylamino 47 4-(pyrrolidin-1-yl)piperazin-1-yl 484-(3-trifluoromethylphenyl)piperazin-1-yl 494-(benzyloxycarbonyl)piperazin-1-yl 504-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl 51 4-benzylpiperazin-1-yl 524-(3,4-methylenedioxybenzyl)piperazin-1-yl 53 4-phenylpiperazin-1-yl 544-(3-phenylprop-2-enyl)piperazin-1-yl 55 4-ethylpiperazin-1-yl 562-(dimethylamino)ethylamino 574-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl 584-(1-methylpiperidin-4-yl)piperazin-1-yl 59 4-butylpiperazin-1-yl 604-isopropylpiperazin-1-yl 61 4-pyridylmethylamino 623-(dimethylamino)propylamino 63 1-benzylpiperidin-4-ylamino 64N-benzyl-2-(dimethylamino)ethylamino 65 3-pyridylmethylamino 664-(cyclohexyl)piperazin-1-yl 67 4-(2-cyclohexylethyl)piperazin-1-yl 684-[2-(morpholin-4-yl)ethyl]piperazin-1-yl 694-(4-tert-butylbenzyl)piperazin-1-yl 704-[2-(piperidin-1-yl)ethyl]piperazin-1-yl 714-[3-(piperidin-1-yl)propyl]piperazin-1-yl 724-[2-(N,N-dipropylamino)ethyl]piperazin-1-yl 734-[3-(N,N-diethylamino)propyl]piperazin-1-yl 744-[2-(dimethylamino)ethyl]piperazin-1-yl 754-[3-(pyrrolidin-1-yl)propyl]piperazin-1-yl 764-(cyclohexylmethyl)piperazin-1-yl 77 4-cyclopentylpiperazin-1-yl 784-[2-(pyrrolidin-1-yl)ethyl]piperazin-1-yl 794-[2-(thien-2-yl)ethyl]piperazin-1-yl 804-(3-phenylpropyl)piperazin-1-yl 814-[2-(N,N-diethylamino)ethyl]piperazin-1-yl 824-benzylhomopiperazin-1-yl 83 4-(bisphenylmethyl)piperazin-1-yl 843-(4-methylpiperazin-1-yl)propylamino 85(+)-3(S)-1-benzylpyrrolidin-3-ylamino 86 2-pyridylmethylamino   86A4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl

Examples 87–120 and 120A–120D, shown in Table 8, were prepared using theprocedure of Example 6, except that N-benzyloxycarbonyl-D-aspartic acidβ-t-butyl ester monohydrate was replaced with Example 29, and3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine;all listed Examples exhibited an ¹H NMR spectrum consistent with theassigned structure.

TABLE 8

Example A′ 87 2-(piperidin-1-yl)ethylamino 884-(piperidin-1-yl)piperidin-1-yl 89 2-(pyrid-2-yl)ethylamino 90morpholin-4-ylamino 91 4-(pyrrolidin-1-yl)piperazin-1-yl 924-(3-trifluorophenyl)piperazin-1-yl 934-(benzyloxycarbonyl)piperazin-1-yl 944-[2-(2-hydroxylethoxy)ethyl]piperazin-1-yl 95 4-benzylpiperazin-1-yl 964-(3,4-methylenedioxybenzyl)piperazin-1-yl 97 4-phenylpiperazin-1-yl 984-(3-phenylprop-2-enyl)piperazin-1-yl 99 4-ethylpiperazin-1-yl 1002-(dimethylamino)ethylamino 1014-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl 1024-(1-methylpiperidin-4-yl)piperazin-1-yl 103 4-butylpiperazin-1-yl 1044-isopropylpiperazin-1-yl 105 4-pyridylmethylamino 1063-(dimethylamino)propylamino 107 1-benzylpiperidin-4-ylamino 108N-benzyl-2-(dimethylamino)ethylamino 109 3-pyridylmethylamino 1104-cyclohexylpiperazin-1-yl 111 4-(2-cyclohexylethyl)piperazin-1-yl 1124-[2-(morpholin-4-yl)ethyl]piperazin-1-yl 1134-(4-tert-butylbenzyl)piperazin-1-yl 1144-[2-piperidin-1-yl)ethyl]piperazin-1-yl 1154-[3-(piperidin-1-yl)propyl]piperazin-1-yl 1164-[2-(diisopropylamino)ethyl]piperazin-1-yl 1174-[3-(diethylamino)propyl]piperazin-1-yl 1184-(2-dimethylaminoethyl)piperazin-1-yl 1194-[3-(pyrrolidin-1-yl)propyl]piperazin-1-yl 1204-(cyclohexylmethyl)piperazin-1-yl   120A4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl   120B 4-propyl-piperazin-1-yl  120C 4-[N-(isopropyl)acetamid-2-yl]piperazin-1-yl   120D3-benzyl-hexahydro-(1H)-1,3-diazepin-1-yl

Examples 121–132, shown in Table 9, were prepared using the procedure ofExample 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butylester monohydrate was replaced with Example 30, and3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine;all listed Examples exhibited an ¹H NMR spectrum consistent with theassigned structure.

TABLE 9

Example A′ 121 3-trifluoromethylbenzylamino 122 morpholin-4-ylamino 1232-(dimethylamino)ethylamino 124 3-(dimethylamino)propylamino 125cyclohexylamino 126 piperidin-1-yl 127 2-methoxyethylamino 128isopropylamino 129 isobutylamino 130 ethylamino 131 dimethylamino 132methylamino

Examples 133–134 and 134A–134F, shown in Table 10, were prepared usingthe procedure of Example 6, except that N-benzyloxycarbonyl-D-asparticacid β-t-replaced butyl ester monohydrate was replaced with Example 32,and 3-(trifluoromethyl)benzyl amine was replaced with the appropriateamine; all listed Examples exhibited an ¹H NMR spectrum consistent withthe assigned structure.

TABLE 10

Example A′ 133   4-(piperidin-1-yl)piperidin-1-yl 134  4-(2-phenylethyl)piperazin-1-yl 134A4-[2-(piperidin-1-yl)ethyl]piperidin-1-yl 134B4-(pyrrolidin-1-yl)piperazin-1-yl 134C 1-benzylpiperidin-4-ylamino 134D(pyridin-3-ylmethyl)amino 134E 3-(dimethylamino)propylamino 134F3-(S)-(1-benzylpyrrolidin-3-yl)amino

Examples 135–140, shown in Table 11, were prepared using the procedureof Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butylester monohydrate was replaced with Example 33, and3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine;all listed Examples exhibited an ¹H NMR spectrum consistent with theassigned structure.

TABLE 11

Example A′ 135 4-(piperidin-1-yl)piperidin-1-yl 1364-(2-phenylethyl)piperazin-1-yl 137 4-butylpiperazin-1-yl 1384-isopropylpiperazin-1-yl 139 4-cyclohexylpiperazin-1-yl 1404-(cyclohexylmethyl)piperazin-1-yl

Examples 141–171, shown in Table 12, were prepared using the procedureof Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butylester monohydrate was replaced with Example 34, and3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine;all listed Examples exhibited an ¹H NMR spectrum consistent with theassigned structure.

TABLE 12

Example A′ 141 benzylamino 142 (2-methylbenzyl)amino 143(3-methylbenzyl)amino 144 (4-methylbenzyl)amino 145(α-methylbenzyl)amino 146 N-benzyl-N-methylamino 147N-benzyl-N-(t-butyl)amino 148 N-benzyl-N-butylamino 149(3,5-dimethylbenzyl)amino 150 (2-phenylethyl)amino 151 dimethylamino 152(3-trifluoromethoxybenzyl)amino 153 (3,4-dichlorobenzyl)amino 154(3,5-dichlorobenzyl)amino 155 (2,5-dichlorobenzyl)amino 156(2,3-dichlorobenzyl)amino 157 (2-fluoro-5-trifluoromethylbenzyl)amino158 (4-fluoro-3-trifluoromethylbenzyl)amino 159(3-fluoro-5-trifluoromethylbenzyl)amino 160(2-fluoro-3-trifluoromethylbenzyl)amino 161(4-chloro-3-trifluoromethylbenzyl)amino 162 indan-1-ylamino 1634-(2-hydroxybenzimidazol-1-yl)-piperidin-1-yl 1643(S)-(tert-butylaminocarbonyl)-1,2,3,4-tetrahydroisoquino- lin-2-yl 165(3,3-dimethylbutyl)amino 166 4-hydroxy-4-phenylpiperidin-1-yl 167(cyclohexylmethyl)amino 168 (2-phenoxyethyl)amino 1693,4-methylenedioxybenzylamino 170 4-benzylpiperidin-1-yl 171(3-trifluoromethylphenyl)amino

Examples 172–221, shown in Table 13, were prepared using the procedureof Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butylester monohydrate was replaced with Example 34A, and3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine;all listed Examples exhibited an ¹H NMR spectrum with the assignedstructure.

TABLE 13

Example A 172 (3-trifluoromethoxybenzyl)amino 173(3,4-dichlorobenzyl)amino 174 (3,5-dichlorobenzyl)amino 175(2,5-dichlorobenzyl)amino 176 (2,3-dichlorobenzyl)amino 177(2-fluoro-5-trifluoromethylbenzyl)amino 178(4-fluoro-3-trifluoromethylbenzyl)amino 179(3-fluoro-5-trifluoromethylbenzyl)amino 180(2-fluoro-3-trifluoromethylbenzyl)amino 181(4-chloro-3-trifluoromethylbenzyl)amino 182(2-trifluoromethylbenzyl)amino 183 (3-methoxybenzyl)amino 184(3-fluorobenzyl)amino 185 (3,5-difluorobenzyl)amino 186(3-chloro-4-fluorobenzyl)amino 187 (3-chlorobenzyl)amino 188[3,5-bis(trifluoromethyl)benzyl]amino 189 (3-nitrobenzyl)amino 190(3-bromobenzyl)amino 191 benzylamino 192 (2-methylbenzyl)amino 193(3-methylbenzyl)amino 194 (4-methylbenzyl)amino 195(α-methylbenzyl)amino 196 (N-methylbenzyl)amino 197(N-tert-butylbenzyl)amino 198 (N-butylbenzyl)amino 199(3,5-dimethylbenzyl)amino 200 (2-phenylethyl)amino 201(3,5-dimethoxybenzyl)amino 202 (1R)-(3-methoxyphenyl)ethylamino 203(1S)-(3-methoxyphenyl)ethylamino 204 (α,α-dimethylbenzyl)amino 205N-methyl-N-(3-trifluoromethylbenzyl)amino 206 [(S)-α-methylbenzyl]amino207 (1-phenylcycloprop-1yl)amino 208 (pyridin-2-ylmethyl)amino 209(pyridin-3-ylmethyl)amino 210 (pyridin-4-ylmethyl)amino 211(fur-2-ylmethyl)amino 212 [(5-methylfur-2-yl)methyl]amino 213(thien-2-ylmethyl)amino 214 [(S)-1,2,3,4-tetrahydro-1-naphth-1-yl]amino215 [(R)-1,2,3,4-tetrahydro-1-naphth-1-yl]amino 216 (indan-1-yl)amino217 (1-phenylcyclopent-1-yl)amino 218(α,α-dimethyl-3,5-dimethoxybenzyl)amino 219 (2,5-dimethoxybenzyl)amino220 (2-methoxybenzyl)amino 221 (α,α,2-trimethylbenzyl)amino

EXAMPLE 2222(R)-[[4-(Piperidin-1-yl)piperidin-1-yl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(2-fluoro-3-trifluoromethylbenzyl)carboxamide

Example 222 was prepared using the procedure of Example 6, except thatN-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate wasreplaced with Example 34B, and 3-(trifluoromethyl)benzyl amine wasreplaced with 4-(piperidin-1-yl)piperidine; Example 222 exhibited an ¹HNMR spectrum consistent with the assigned structure.

EXAMPLE 2232(R)-[[4-(Piperidin-1-yl)piperidin-1-yl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-[(S)-α-methylbenzyl]amide

Example 223 was prepared using the procedure of Example 6, except thatN-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate wasreplaced with Example 34C, and 3-(trifluoromethyl)benzyl amine wasreplaced with 4-(piperidin-1-yl)piperidine; Example 223 exhibited an ¹HNMR spectrum consistent with the assigned structure.

EXAMPLE 2242(R)-[[4-(Piperidin-1-yl)piperidin-1-yl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-[(R)-α-methylbenzyl]amide

Example 224 was prepared using the procedure of Example 6, except thatN-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate wasreplaced with Example 34D, and 3-(trifluoromethyl)benzyl amine wasreplaced with 4-(piperidin-1-yl)piperidine; Example 223 exhibited an ¹HNMR spectrum consistent with the assigned structure.

EXAMPLE 2252(R)-[[4-(Piperidin-1-yl)piperidin-1-yl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-methyl-N-(3-trifluoromethylbenzyl)amide

Example 225 was prepared using the procedure of Example 6, except thatN-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate wasreplaced with Example 34E, and 3-(trifluoromethyl)benzyl amine wasreplaced with 4-(piperidin-1-yl)piperidine; Example 223 exhibited an ¹HNMR spectrum consistent with the assigned structure.

Examples 226–230, shown in Table 14, were prepared using the procedureof Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butylester monohydrate was replaced with Example 34F, and3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine;all listed Examples exhibited an ¹H NMR spectrum consistent with theassigned structure.

TABLE 14

Example A′ 226 4-cyclohexylpiperazin-1-yl 2274-(pyrrolidin-1-yl)piperazin-1-yl 228 4-ethylpiperazin-1-yl 2294-n-butylpiperazin-1-yl 230 4-isopropylpiperazin-1-yl

EXAMPLE 2312(R)-[[4-(Piperidin-1-yl)piperidin-1-yl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2′-methoxystyr-2-yl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 231 was prepared using the procedure of Example 6, except thatN-benzyloxycarbonyl-D-aspartic acid β-t-butyl ester monohydrate wasreplaced with Example 34G, and 3-(trifluoromethyl)benzyl amine wasreplaced with 4-(piperidin-1-yl)piperidine; Example 231 exhibited an ¹HNMR spectrum consistent with the assigned structure.

Examples 232–233, shown in Table 15, were prepared using the procedureof Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-t-butylester monohydrate was replaced with Example 34H, and3-(trifluoromethyl)benzyl amine was replaced with the appropriate amine;all listed Examples exhibited an ¹H NMR spectrum consistent with theassigned structure.

TABLE 15

Example A′ 232 4-(piperidin-1-yl)piperidin-1-yl 2334-[2-(piperidin-1-yl)ethyl]piperidin-1-yl

EXAMPLE 234(2RS)-[4-(piperidin-1-yl)piperidin-1-ylcarbonyl]-2-methyl-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 37 (50 mg, 0.067 mmol) in tetrahydrofuran (4 mL) was treatedsequentially with sodium hydride (4 mg, 0.168 mmol) and methyl iodide (6μL, 0.094 mmol) at −78° C. The resulting mixture was slowly warmed toambient temperature, and evaporated. The resulting residue waspartitioned between dichloromethane and water, and the organic layer wasevaporated. The resulting residue was purified by silica gelchromatography (95:5 chloroform/methanol) to give 28 mg (55%) of thetitle compound as an off-white solid; MS (ES⁺): m/z=757 (M⁺).

EXAMPLE 2352(S)-[[(1-Benzylpiperidin-4-yl)amino]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenyleth-1-yl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 235 was prepared using the procedure of Example 8, except thatN-benzyloxycarbonyl-L-aspartic acid β-t-butyl esterα-(3-trifluoromethyl)benzylamide was replaced with Example 63 (50 mg,0.064 mmol) to give 40 mg (80%) of Example 235 as an off-white solid;Example 235 exhibited an ¹H NMR spectrum consistent with the assignedstructure.

EXAMPLE 236(2S)-[(4-cyclohexylpiperazin-1-yl)carbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenyleth-1-yl)azetidin-2-on-1-yl]aceticacid N-(3-trifluoromethylbenzyl)amide

Example 236 was prepared using the procedure of Example 8, except thatN-benzyloxycarbonyl-L-aspartic acid β-t-butyl esterα-(3-trifluoromethyl)benzylamide was replaced with Example 110 (50 mg,0.065 mmol) to give 42 mg (84%) of Example 236 as an off-white solid;Example 236 exhibited an ¹H NMR spectrum consistent with the assignedstructure.

Table 16 illustrates compounds further characterized by mass spectralanalysis using FAB⁺ to observe the corresponding (M+H)⁺ parent ion.

TABLE 16 Example (m + H)⁺/z  37 744  38 766  39 766  40 718  41 704  42744  42A 772  44 758  63 780  85 766  86A 786  88 772  91 759  95 780 96 824 104 732 110 772 111 800 112 803 120 786 120A 800 120B 732 133758 134A 786 134C 780 136 794 137 746 138 732 139 772 174 772 175 772176 772 177 790 179 790 180 790 182 772 183 734 184 722 185 740 186 756187 738 188 840 189 749 190 782 191 704 192 718 193 718 199 732 200 718201 764 202 748 203 748 205 786 206 718 207 730 208 705 209 705 210 705211 694 212 708 213 710 214 744 215 744 216 7530 217 758 218 792 219 764220 734 221 746 222 776 224 704 225 772 226 806 227 792 228 752 229 780230 766 231 788 232 663 233 691 234 758 235 782 236 774

METHOD EXAMPLE 1 Human Vasopression V_(1a) Receptor Binding Assay

A cell line expressing the human V_(1a) receptor in CHO cells(henceforth referred to as the hV_(1a) cell line) was obtained from Dr.Michael Brownstein, NIMH, Bethesda, Md., USA. The hV_(1a) cDNA sequenceis described by Thibonnier et al., Journal of Biological Chemistry, 269,3304–3310 (1994), and the expression method was the same as described byMorel et al. (1992). The hV_(1a) cell line was grown in alpha-MEM with10% fetal bovine serum and 250 ug/ml G418 (Gibco, Grand Island, N.Y.,USA). For competitive binding assay, hV1a cells were plated into 6-wellculture plate at 1:10 dilution from a confluency flask, and maintainedin culture for at least two days. Culture medium was then removed, cellswere washed with 2 ml binding buffer (25 mM Hepes, 0.25% BSA, 1×DMEM,PH=7.0). To each well, 990 μl binding buffer containing 1 nM 3H-AVP wasadded, and followed by 10 μl series diluted Example compounds dissolvedin DMSO. All incubations were in triplicate, and dose-inhibition curvesconsisted of total binding (DMSO) and 5 concentrations (0.1, 1.0, 10,100, and 1000 nM) of test agents encompassing the IC₅₀. 100 nM cold AVP(Sigma) was used to assess non-specific binding. Cells were incubatedfor 45 minutes at 37° C., assay mixture was removed and each well waswashed three times with PBS (pH=7.4). 1 ml 2% SDS was added per well andplates were let sit for 30 minutes. The whole content in a well wastransferred to a scintillation vial. Each well was rinsed with 0.5 mlPBS which was then added to the corresponding vial. Scintillation fluid(Ecoscint, National Diagnostics, Atlanta, Ga.) was then added at 3 mlper vial. Samples were counted in a liquid scintillation counter(Beckman LS3801). IC₅₀ values were calculated by Prism Curve fittingsoftware.

All of the alkanedioic esters and amides exemplified in the foregoingexamples were tested in this assay described of Example 201. Bindingaffinities for certain of the preferred compounds are summarized in theTable 17.

TABLE 17 V_(1a) BINDING AFFINITY Example (IC₅₀ (nM)) 18 35 19 35 20 3535 1.9 37 5.5 38 <25 39 23 40 11 41 <20 42 <20 44 3.1 47 ~50 59 <100 631.84 66 ~50 77 <100 78 <100 81 <100 82 <50 85 5.87 87 15 88 2.4 91 3.2495 1.76 96 4.35 100 <100 101 ~100 102 <100 103 0.81 104 1.85 106 ~100107 <50 108 ~100 109 ~100 110 0.49 111 1.31 112 1.34 120 0.75 133 2.43135 ~50 136 11 137 17 138 21 139 9.5

METHOD EXAMPLE 2 Inhibition of Phosphatidylinositol Turnover

The physiological effects of vasopressin are mediated through specificG-protein coupled receptors. The vasopressin V_(1a) receptor is coupledto the G_(q)/G₁₁ family of G proteins and mediates phosphatidylinositolturnover. The agonist or antagonist character of the compounds of theinvention may be determined by their ability to inhibitvasopressin-mediated turnover of phosphatidylinositol by the proceduredescribed in the following paragraphs. Representative compounds of theinvention, the compounds of Examples 35, 44, 88, 110, and 133, weretested in this assay and found to be vasopressin V_(1a) antagonists.

Cell Culture and Labeling of Cells.

Three days prior to the assay, near-confluent cultures of hV1a cellswere dissociated and seeded in 6-well tissue culture plates, about 100wells being seeded from each 75 cm² flask (equivalent to 12:1 splitratio). Each well contained 1 mL of growth medium with 2 μCi of[³H]myo-inositol (American Radiolabeled Chemicals, St. Louis, Mo., USA).

Incubations

All assays were in triplicate except for basal and 10 nM AVP (both n=6).AVP ((arginine vasopressin), Peninsula Labs, Belmont, Calif., USA(#8103)) was dissolved in 0.1N acetic acid. Test agents were dissolvedin DMSO and diluted in DMSO to 200 times the final test concentration.Test agents and AVP (or corresponding volumes of DMSO) were addedseparately as 5 μL in DMSO to 12×75 mm glass tubes containing 1 mL ofassay buffer (Tyrode's balanced salt solution containing 50 mM glucose,10 mM LiCl, 15 mM HEPES pH 7.4, 10 μM phosphoramidon, and 100 μMbacitracin). The order of incubations was randomized. Incubations wereinitiated by removing the prelabeling medium, washing the monolayer oncewith 1 mL of 0.9% NaCl, and transferring the contents of the assay tubesto corresponding wells. The plates were incubated for 1 hour at 37° C.Incubations were terminated by removing the incubation medium and adding500 μL of ice cold 5% (w/v) trichloroacetic acid and allowing the wellsto stand for 15 min.

Measurement of [³H]inositol Phosphates

BioRad Poly-Prep Econo-Columns were packed with 0.3 mL of AG 1 X-8100–200 formate form resin. Resin was mixed 1:1 with water and 0.6 mLadded to each column. Columns were then washed with 10 mL water.Scintillation vials (20 mL) were placed under each column. For eachwell, the contents were transferred to a minicolumn, after which thewell was washed with 0.5 mL distilled water, which was also added to theminicolumn. The columns were then washed twice with 5 mL of 5 mMmyo-inositol to elute free inositol. Aliquots (1 mL) were transferred to20 mL scintillation vials and 10 mL of Beckman Ready Protein Plus added.After the myo-inositol wash was complete, empty scintillation vials wereplaced under the columns, and [³H]inositol phosphates were eluted withthree additions of 1 mL 0.5 M ammonium formate containing 0.1 N formicacid. Elution conditions were optimized to recover inositol mono-, bis-,and trisphosphates, without eluting the more metabolically inerttetrakis-, pentakis-, and hexakis-phosphates. To each sample was added10 mL of a high salt capacity scintillation fluid such as Tru-Count HighSalt Capacity or Packard Hionic-Fluor. Inositol lipids were measured byadding 1 mL of 2% sodium dodecyl sulfate (SDS) to each well, allowingthe wells to stand for at least 30 min., and transferring the solutionto 20 mL scintillation vials, to which 10 mL Beckman Ready Protein Plusscintillation fluid was then added. Samples were counted in a Beckman LS3801 liquid scintillation counter for 10 min. Total inositolincorporation for each well was calculated as the sum of free inositol,inositol phosphates, and inositol lipids.

Data Analysis: Concentration-inhibition Experiments

Concentration-response curves for AVP and concentration-inhibitioncurves for test agents versus 10 nM AVP were analyzed by nonlinearleast-squares curve-fitting to a 4-parameter logistic function.Parameters for basal and maximal inositol phosphates, EC₅₀ or IC₅₀, andHill coefficient were varied to achieve the best fit. The curve-fittingwas weighted under the assumption that the standard deviation wasproportional to dpm of radioactivity. Full concentration-response curvesfor AVP were run in each experiment, and IC₅₀ values were converted toK_(i) values by application of the Cheng-Prusoff equation, based on theEC₅₀ for AVP in the same experiment. Inositol phosphates were expressedas dpm per 10⁶ dpm of total inositol incorporation.

Data Analysis: Competitivity Experiments

Experiments to test for competitivity of test agents consisted ofconcentration-response curves for AVP in the absence and presence of twoor more concentrations of test agent. Data were fit to a competitivelogistic equation

$Y = {B + \frac{M \times \left\{ {A/\left\lbrack {E + \left( {D/K} \right)} \right\rbrack} \right\}^{Q}}{1 + \left\{ {A/\left\lbrack {E + \left( {D/K} \right)} \right\rbrack} \right\}^{Q}}}$where Y is dpm of inositol phosphates, B is concentration of basalinositol phosphates, M is the maximal increase in concentration ofinositol phosphates, A is the concentration of agonist (AVP), E is theEC₅₀ for agonist, D is the concentration of antagonist (test agent), Kis the K_(i) for antagonist, and Q is the cooperativity (Hillcoefficient).

Vasopressin V_(1a) receptors are also known to mediate plateletaggregation. Vasopressin V_(1a) receptor agonists cause plateletaggregation, while vasopressin V_(1a) receptor antagonists inhibit theplatelet aggregation precipitated by vasopressin or vasopressin V_(1a)agonists. The degree of antagonist activity of the compounds of theinvention may be determined by the assay described in the followingparagraphs.

Blood from healthy, human volunteers was collected by venipuncture andmixed with heparin (60 mL of blood added to 0.4 mL of heparanized salinesolution (4 mg heparin/mL saline)). Platelet-rich plasma (PRP) wasprepared by centrifuging whole blood (150×g), and indomethacin (3 μM)was added to PRP to block the thromboxane-mediated release reaction. PRPwas continuously stirred at 37° C. and change in optical density wasfollowed after the addition of arginine vasopressin (AVP) (30 nM) toinitiate aggregation. Compounds were dissolved in 50% dimethylsulfoxide(DMSO) and added (10 μL/415 μL PRP) before the addition of AVP. Thepercent inhibition of AVP-induced aggregation was measured and an IC₅₀calculated.

In studies using washed platelets, 50 mL of whole blood was mixed with10 mL of citrate/heparin solution (85 mM sodium citrate, 64 mM citricacid, 111 mM glucose, 5 units/mL heparin) and PRP isolated as describedabove. PRP was then centrifuged (150×g) and the pellet resuspended in aphysiologic buffer solution (10 mM HEPES, 135 mM sodium chloride, 5 mMpotassium chloride, and 1 mM magnesium chloride) containing 10 μMindomethicin. Human fibrinogen (0.2 mg/mL) and calcium chloride (1 mM)were added to stirred platelets before initiating aggregation with AVP(30 nM) as previously described.

The activity of compounds of formula I in the antagonism of thevasopressin V_(1a) receptor provides a method of antagonizing thevasopressin V_(1a) receptor comprising administering to a subject inneed of such treatment an effective amount of a compound of thatformula. It is known that numerous physiological and therapeuticbenefits are obtained through the administration of drugs thatantagonize the vasopressin V_(1a) receptor. These activities may becatagorized as peripheral and central. Peripheral utilities includeadministration of vasopressin V_(1a) antagonists of formula I asadjuncts in heart failure or as antithrombotic agents. Central effectsinclude administration of vasopressin V_(1a) antagonists of formula I inthe treatment of obsessive-compulsive disorder, aggressive disorders,depression and anxiety.

Obsessive-compulsive disease appears in a great variety of degrees andsymptoms, generally linked by the victim's uncontrollable urge toperform needless, ritualistic acts. Acts of acquiring, ordering,cleansing and the like, beyond any rational need or rationale, are theoutward characteristic of the disease. A badly afflicted subject may beunable to do anything but carry out the rituals required by the disease.Obsessive-compulsive disease, in all its variations, is a preferredtarget of treatment with the present adjunctive therapy method andcompositions. The utility of the compounds of Formula I in the treatmentof obsessive-compulsive disorder was demonstrated as described in thefollowing assay.

In golden hamsters, a particular stereotypy, flank marking behavior, canbe induced by microinjections of vasopressin (10–100 nL, 1–100 μM) intothe anterior hypothalamus (Ferris et al., Science, 224, 521–523 (1984);Albers and Ferris, Regulatory Peptides, 12, 257–260 (1985); Ferris etal., European Journal of Pharmacology, 154, 153–159 (1988)). Followingthe releasing stimulus, the behavior is initiated by grooming, lickingand combing of the large sebaceous glands on the dorsolateral flanks.Bouts of flank gland grooming may be so intense that the flank region isleft matted and soaked in saliva. After grooming, the hamsters displayflank marking behavior, a type of scent marking involved in olfactorycommunication (Johnston, Physio. Behav., 51, 437–448 (1985); Ferris etal., Physio. Behav., 40, 661–664 (1987)), by arching the back andrubbing the flank glands vigorously against any vertical surface.Vasopressin-induced flank marking is usually induced within a minuteafter the microinjection (Ferris et al., Science, 224, 521–523 (1984)).The behavior is specific to vasopressin, as micro-injections of otherneuropeptides, excitatory amino acids, and catecholamines do not elicitflank marking (Ferris et al., Science, 224, 521–523 (1984); Albers andFerris, Regulatory Peptides, 12, 257–260 (1985)). Furthermore, flankmarking is specific to the vasopressin V₁ receptor, as the behavior isselectively inhibited by V₁ receptor antagonists and activated by V₁receptor agonists (Ferris et al., Neuroscience Letters, 55, 239–243(1985); Albers et al., Journal of Neuroscience, 6, 2085–2089 (1986);Ferris et al., European Journal of Pharmacology, 154, 153–159 (1988)).

All animals were adult male golden hamsters (Mesocricetus auratus)weighing approximately 160 gm. The animals underwent stereotaxicsurgery, and were allowed to recover before behavioral testing. Thehamsters were kept on a reverse light cycle (14 hr light, 10 hr dark,lights on at 19:00) in Plexiglas™ cages, and received food and water adlibitum.

Stereotaxic surgery was performed under pentobarbital anesthesia. Thestereotaxic coordinates were: 1.1 mm anterior to the bregma, 1.8 mmlateral to the midsagittal suture at an 8° angle from the verticle line,and 4.5 mm below the dura. The nose bar was placed at the level of theinteraural line. An unilateral 26-gauge guide cannula was lowered to thesite and secured to the skull with dental cement. The guide cannulaewere closed with a 33-gauge obturator extending 1 mm beyond the guide.The innercanulae used for the microinjections extended 3.0 mm beyond theguide to reach the anterior hypothalamus.

The hamsters were microinjected with 1 μM vasopressin in a volume of 150nL. The vasopressin was given as a cocktail with 200 mM, 20 mM, 2 mM ofthe test compound or alone, in the vehicle, dimethylsulfoxide. Both thevasopressin and the test compound were dissolved in 100%dimethylsulfoxide. All injections were aimed at the anteriorhypothalamus. Animals were scored for flank marking for a period of 10minutes in a clean cage.

Another aspect of this invention is the use of compounds of formula I incombination with a serotonin reuptake inhibitor for use in the treatmentof obsessive-compulsive disease, aggressive disorder, or depression.Compounds useful as serotonin reuptake inhibitors include but are notlimited to:

Fluoxetine, N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine,is marketed in the hydrochloride salt form, and as the racemic mixtureof its two enantiomers. U.S. Pat. No. 4,314,081 is an early reference onthe compound. Robertson et al., J. Med. Chem., 31, 1412 (1988), taughtthe separation of the R and S enantiomers of fluoxetine and showed thattheir activity as serotonin uptake inhibitors is similar to each other.In this document, the word “fluoxetine” will be used to mean any acidaddition salt or the free base, and to include either the racemicmixture or either of the R and S enantiomers;

Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, isusually administered as the hydrochloride salt and as the (+)enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which showsits high potency. The word “duloxetine” will be used here to refer toany acid addition salt or the free base of the molecule;

Venlafaxine is known in the literature, and its method of synthesis andits activity as an inhibitor of serotonin and norepinephrine uptake aretaught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compoundA in that patent;

Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide)is taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as itsExample 4. The patent describes its compounds as antidepressants. Moretet al., Neuropharmacology, 24, 1211–19 (1985), describe itspharmacological activities as an inhibitor of serotonin andnorepinephrine reuptake;

Citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,is disclosed in U.S. Pat. No. 4,136,193 as a serotonin reuptakeinhibitor. Its pharmacology was disclosed by Christensen et al., Eur. J.Pharmacol., 41, 153 (1977), and reports of its clinical effectiveness indepression may be found in Dufour et al., Int. Clin. Psychopharmacol.,2, 225 (1987), and Timmerman et al., ibid., 239;

Fluvoxamine, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanoneO-(2-aminoethyl)oxime, is taught by U.S. Pat. No. 4,085,225. Scientificarticles about the drug have been published by Claassen et al., Brit. J.Pharmacol., 60, 505 (1977); and De Wilde et al., J. Affective Disord.,4, 249 (1982); and Benfield et al., Drugs, 32, 313 (1986);

Paroxetine,trans-(−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine,may be found in U.S. Pat. Nos. 3,912,743 and 4,007,196. Reports of thedrug's activity are in Lassen, Eur. J. Pharmacol., 47, 351 (1978);Hassan et al., Brit. J. Clin. Pharmacol., 19, 705 (1985); Laursen etal., Acta Psychiat. Scand., 71, 249 (1985); and Battegay et al.,Neuropsychobiology, 13, 31 (1985); and

Sertraline,(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylaminehydrochloride, a serotonin reuptake inhibitor disclosed in U.S. Pat. No.4,536,518, is marketed as an antidepressant.

All of the above-referenced patents are hereby incorporated byreference.

The adjunctive therapy of this aspect of the present invention iscarried out by administering a vasopressin V_(1a) antagonist togetherwith a serotonin reuptake inhibitor in any manner that provideseffective levels of the compounds in the body at the same time. All ofthe compounds concerned are orally available and are normallyadministered orally, and so oral administration of the adjunctivecombination is preferred. They may be administered together, in a singledosage form, or may be administered separately.

This aspect of the present invention provides a potentiation of thedecrease in the concentration of vasopressin observed as an effect ofadministration of a vasopressin V_(1a) antagonist by administration of aserotonin reuptake inhibitor. This aspect of the present invention isparticularly suited for use in the treatment of depression and obsessivecompulsive disorder. Such disorders may often be resistant to treatmentwith a serotonin reuptake inhibitor alone.

METHOD EXAMPLE 3 Human Oxytocin Binding and Functional Assay

Compounds of the present invention are believed to be oxytocin agents.Oxytocin preparations and a number of oxytocin agonists are commerciallyavailable for therapeutic use. In recent years, oxytocin antagonistswith antiuterotonic activity have been developed and evaluated for theirpotential use in the treatment of preterm labor and dysmenorrhyea (Pavoet al., J. Med. Chem., 37, 255–259 (1994); Akerlund et al., Br. J.Obstet. Gynaecol., 94, 1040–1044 (1987); Akerlund et al., Br. J. Obstet.Gynaecol., 86, 484–487 (1979)). The oxytocin antagonist atosiban hasbeen studied clinically and resulted in a more significant inhibition ofpreterm contractions than did placebo (Goodwin et al., Am. J. Obstet.Gynecol., 170, 474 (1994)).

The human oxytocin receptor has been cloned and expressed (Kimura etal., Nature, 356, 526–529 (1992)), it is identified under the accessionnumber X64878. To demonstrate the affinity of the compounds of thepresent invention for the human oxytocin receptor, binding studies wereperformed using a cell line expressing the human oxytocin receptor in293 cells (henceforth referred to as the OTR cell line) substantially bythe procedure described by Morel et al. (Nature, 356, 523–526 (1992)).The 293 cell line is a permanent line of primary human embryonal kidneycells transformed by sheared human adenovirus type 5 DNA. It isidentified as ATCC CRL-1533.

The OTR cell line was grown in DMEM (Delbecco's Modified EssentialMedium, Sigma, St. Louis, Mo., USA) with 10% fetal bovine serum, 2 mML-glutamine, 200 μg hygromycin (Sigma, St. Louis, Mo., USA) and 250μg/ml G418 (Gibco, Grand Island, N.Y., USA). To prepare membranes, OTRcells were grown to confluency in 20 roller bottles. Cells weredissociated with enzyme-free cell dissociation medium (Specialty Media,Lavallette, N.J., USA) and centrifuged at 3200 rpm for 15 minutes. Thepellet was resuspended in 40 mL of Tris-HCl(tris[hydroxymethyl]aminomethane hydrochloride) buffer (50 mM, pH 7.4)and homogenized for 1 minute with a Tekmar Tissumizer (Cincinnatti, OhioUSA). The suspension was centrifuged at 40,000×g for 10 minutes. Thepellet was resuspended and centrifuged as above. The final pellet wassuspended in 80 mL of Tris 7.4 buffer and stored in 4 ML aliquots at−80° C. For assay, aliquots were resuspended in assay buffer and dilutedto 375 μg protein per mL. Protein concentration was determined by BCAassay (Pierce, Rockford, Ill., USA).

Assay buffer was 50 mM Tris-HCl (tris[hydroxymethyl]aminomethanehydrochloride), 5 mM MgCl₂, and 0.1% bovine serum albumin at pH 7.4. Theradioligand for binding assays was [³H]oxytocin([tyrosyl-2,6-³H]oxytocin, 48.5 Ci/mmol, DuPont NEN, Boston, Mass.,USA). The order of additions was 195 μL assay buffer, 200 μL OTRmembranes (75 μg protein) in assay buffer, 5 μL of test agent indimethylsulfoxide (DMSO) or DMSO alone, and 100 μL [³H]oxytocin in assaybuffer (final concentration 1.0 nM). Incubations were for one hour atroom temperature. Bound radioligand was separated from free byfiltration on a Brandel cell harvester (Gaithersburg, Md., USA) throughWhatman GF/B glass-fiber filters that had been soaked for 2 hours in0.3% polyethylenimine. The filters were washed with ice-cold 50 mMTris-HCl (pH 7.7 at 25° C.) and the filter circles were placed inscintillation vials, to which were then added 5 mL Ready Protein Plus™scintillation fluid, and counted in a liquid scintillation counter. Allincubations were in triplicate, and dose-inhibition curves consisted oftotal binding, nonspecific binding (100 μM oxytocin, Sigma, St. Louis,Mo., USA), and 6 or 7 concentrations of test agent encompassing theIC₅₀. Total binding was typically about 1,000 cpm and nonspecificbinding about 200 cpm. IC₅₀ values were calculated by nonlinearleast-squares curve-fitting to a 4-parameter logistic model. Certaincompounds of formula I have shown affinity for the oxytocin receptor.

Several bioassays are available to determine the agonist or antagonistcharacter of compounds exhibiting affinity at the oxytocin receptor. Onesuch assay is described in U.S. Pat. No. 5,373,089, hereby incorporatedby reference. Said bioassay is derived from procedures described in apaper by Sawyer et al. (Endocrinology, 106, 81 (1980)), which in turnwas based on a report of Holton (Brit. J. Pharmacol., 3, 328 (1948)).The assay calculations for pA₂ estimates are described by Schild (Brit.J. Pharmacol., 2, 189 (1947)).

Assay Method

1. Animals—a 1.5 cm piece of uterus from a virgin rat (Holtzman) innatural estrus is used for the assay.

2. Buffer/Assay Bath—The buffer used is Munsicks. This buffer contains0.5 mM Mg²⁺. The buffer is gassed continuously with 95% oxygen/5% carbondioxide giving a pH of 7.4. The temperature of the assay bath is 37° C.A 10 mL assay bath is used that contains a water jacket for maintainingthe temperature and inlet and outlet spikets for adding and removingbuffer.

3. Polygraph/transducer—The piece of uterine tissue used for the assayis anchored at one end and connected to a Statham Strain Gauge ForceTransducer at the other end which in turn is attached to a GrassPolygraph Model 79 for monitoring the contractions.

4. Assay Protocol:

(a) The tissue is equilibrated in the assay bath for one hour withwashing with new buffer every 15 minutes. One gram of tension is kept onthe tissue at all times.

(b) The tissue is stimulated initially with oxytocin at 10 nM toacclimate the tissue and with 4 mM potassium chloride (KCl) to determinethe maximum contractile response.

(c) A cumulative dose response curve is then done with oxytocin and aconcentration of oxytocin equivalent to approximately 80% of the maximumis used for estimating the pA₂ of the antagonist.

(d) The tissue is exposed to oxytocin (Calbiochemical, San Diego,Calif.) for one minute and washed out. There is a three minute intervalbefore addition of the next dose of agonist or antagonist. When theantagonist is tested, it is given five minutes before the agonist. Theagonist is given for one minute. All responses are integrated using a7P10 Grass Integrator. A single concentration of oxytocin, equal to 80%of the maximum response, is used to test the antagonist. Three differentconcentrations of antagonists are used, two that will reduce theresponse to the agonist by less than 50% and one that will reduce theresponse greater than 50% (ideally this relation would be 25%, 50% and75%). This is repeated three times for each dose of antagonist for athree point assay.

(e) Calculations for pA₂—The dose-response (DR) ratios are calculatedfor antagonist and a Schild's Plot is performed by plotting the Log(DR-1) vs. Log of antagonist concentration. The line plotted iscalculated by least-squares regression analysis. The pA₂ is theconcentration of antagonist at the point where the regression linecrosses the 0 point of the Log (DR-1) ordinate. The pA₂ is the negativeLog of the concentration of antagonist that will reduce the response tothe agonist by one-half.

Oxytocin is well known for its hormonal role in parturition andlactation. Oxytocin agonists are useful clinically to induce lactation;induce or augment labor; control postpartum uterine atony andhemmorhage; cause uterine contraction after cesarean section or duringother uterine surgery; and to induce therapeutic abortion. Oxytocin,acting as a neurotransmitter in the central nervous system, also playsan important role in the expression of central functions such asmaternal behavior, sexual behavior (including penile erection, lordosisand copulatory behavior), yawning, tolerance and dependance mechanisms,feeding, grooming, cardiovascular regulation and thermoregulation(Argiolas and Gessa, Neuroscience and Biobehavioral Reviews, 15, 217–231(1991)). Oxytocin antagonists find therapeutic utility as agents for thedelay or prevention of premature labor; or to slow or arrest deliveryfor brief periods in order to undertake other therapeutic measures.

METHOD EXAMPLE 4 Tachykinin Receptor Binding Assay

Compounds of the present invention are believed to be tachykinin agents.Tachykinins are a family of peptides which share a common amidatedcarboxy terminal sequence. Substance P was the first peptide of thisfamily to be isolated, although its purification and the determinationof its primary sequence did not occur until the early 1970's. Between1983 and 1984 several groups reported the isolation of two novelmammalian tachykinins, now termed neurokinin A (also known as substanceK, neuromedin 1, and neurokinin α, and neurokinin B (also known asneuromedin K and neurokinin β). See, J. E. Maggio, Peptides, 6(Supplement 3), 237–243 (1985) for a review of these discoveries.

Tachykinins are widely distributed in both the central and peripheralnervous systems. When released from nerves, they exert a variety ofbiological actions, which, in most cases, depend upon activation ofspecific receptors expressed on the membrane of target cells.Tachykinins are also produced by a number of non-neural tissues. Themammalian tachykinins substance P, neurokinin A, and neurokinin B actthrough three major receptor subtypes, denoted as NK-1, NK-2, and NK-3,respectively. These receptors are present in a variety of organs.

Substance P is believed inter alia to be involved in theneurotransmission of pain sensations, including the pain associated withmigraine headaches and with arthritis. These peptides have also beenimplicated in gastrointestinal disorders and diseases of thegastrointestinal tract such as inflammatory bowel disease. Tachykininshave also been implicated as playing a role in numerous other maladies,as discussed infra.

In view of the wide number of clinical maladies associated with anexcess of tachykinins, the development of tachykinin receptorantagonists will serve to control these clinical conditions. Theearliest tachykinin receptor antagonists were peptide derivatives. Theseantagonists proved to be of limited pharmaceutical utility because oftheir metabolic instability. Recent publications have described novelclasses of non-peptidyl tachykinin receptor antagonists which generallyhave greater oral bioavailability and metabolic stability than theearlier classes of tachykinin receptor antagonists. Examples of suchnewer non-peptidyl tachykinin receptor antagonists are found in EuropeanPatent Publication 591,040 A1, published Apr. 6, 1994; PatentCooperation Treaty publication WO 94/01402, published Jan. 20, 1994;Patent Cooperation Treaty publication WO 94/04494, published Mar. 3,1994; Patent Cooperation Treaty publication WO 93/011609, published Jan.21, 1993, Patent Cooperation Treaty publication WO 94/26735, publishedNov. 24, 1994. Assays useful for evaluating tachykinin receptorantagonists are well known in the art. See. e.g., J. Jukic et al., LifeSciences, 49, 1463–1469 (1991); N. Kucharczyk et al., Journal ofMedicinal Chemistry, 36, 1654–1661 (1993); N. Rouissi et al.,Biochemical and Biophysical Research Communications, 176, 894–901(1991).

METHOD EXAMPLE 5 NK-1 Receptor Binding Assay

Radioreceptor binding assays were performed using a derivative of apreviously published protocol. D. G. Payan et al., Journal ofImmunology, 133, 3260–3265 (1984). In this assay an aliquot of IM9 cells(1×10⁶ cells/tube in RPMI 1604 medium supplemented with 10% fetal calfserum) was incubated with 20 pM ¹²⁵I-labeled substance P in the presenceof increasing competitor concentrations for 45 minutes at 4° C.

The IM9 cell line is a well-characterized cell line which is readilyavailable to the public. See, e.g., Annals of the New York Academy ofScience, 190, 221–234 (1972); Nature (London), 251, 443–444 (1974);Proceedings of the National Academy of Sciences (USA), 71, 84–88 (1974).These cells were routinely cultured in RPMI 1640 supplemented with 50μg/mL gentamicin sulfate and 10% fetal calf serum.

The reaction was terminated by filtration through a glass fiber filterharvesting system using filters previously soaked for 20 minutes in 0.1%polyethylenimine. Specific binding of labeled substance P was determinedin the presence of 20 nM unlabeled ligand.

METHOD EXAMPLE 6 NK-2 Receptor Binding Assay

The CHO-hNK-2R cells, a CHO-derived cell line transformed with the humanNK-2 receptor, expressing about 400,000 such receptors per cell, weregrown in 75 cm² flasks or roller bottles in minimal essential medium(alpha modification) with 10% fetal bovine serum. The gene sequence ofthe human NK-2 receptor is given in N. P. Gerard et al., Journal ofBiological Chemistry, 265, 20455–20462 (1990).

For preparation of membranes, 30 confluent roller bottle cultures weredissociated by washing each roller bottle with 10 ml of Dulbecco'sphosphate buffered saline (PBS) without calcium and magnesium, followedby addition of 10 ml of enzyme-free cell dissociation solution(PBS-based, from Specialty Media, Inc.). After an additional 15 minutes,the dissociated cells were pooled and centrifuged at 1,000 RPM for 10minutes in a clinical centrifuge. Membranes were prepared byhomogenization of the cell pellets in 300 mL 50 mM Tris buffer, pH 7.4with a Tekmar® homogenizer for 10–15 seconds, followed by centrifugationat 12,000 RPM (20,000×g) for 30 minutes using a Beckman JA-14® rotor.The pellets were washed once using the above procedure, and the finalpellets were resuspended in 100–120 mL 50 mM Tris buffer, pH 7.4, and 4ml aliquots stored frozen at −70° C. The protein concentration of thispreparation was 2 mg/mL.

For the receptor binding assay, one 4-mL aliquot of the CHO-hNK-2Rmembrane preparation was suspended in 40 mL of assay buffer containing50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin(BSA) and 4 μg/mL chymostatin. A 200 μL volume of the homogenate (40 μgprotein) was used per sample. The radioactive ligand was[¹²⁵I]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200Ci/mmol. The ligand was prepared in assay buffer at 20 nCi per 100 μL;the final concentration in the assay was 20 pM. Non-specific binding wasdetermined using 1 μM eledoisin. Ten concentrations of eledoisin from0.1 to 1000 nM were used for a standard concentration-response curve.

All samples and standards were added to the incubation in 10 μLdimethylsulfoxide (DMSO) for screening (single dose) or in 5 μL DMSO forIC₅₀ determinations. The order of additions for incubation was 190 or195 μL assay buffer, 200 μL homogenate, 10 or 5 μL sample in DMSO, 100μL radioactive ligand. The samples were incubated 1 hr at roomtemperature and then filtered on a cell harvester through filters whichhad been presoaked for two hours in 50 mM Tris buffer, pH 7.7,containing 0.5% BSA. The filter was washed 3 times with approximately 3mL of cold 50 mM Tris buffer, pH 7.7. The filter circles were thenpunched into 12×75 mm polystyrene tubes and counted in a gamma counter.

Tachykinin receptor antagonists are of value in the treatment of a widevariety of clinical conditions which are characterized by the presenceof an excess of tachykinin. These clinical conditions may includedisorders of the central nervous system such as anxiety, depression,psychosis, and schizophrenia; neurodegenerative disorders such asdementia, including senile dementia of the Alzheimer's type, Alzheimer'sdisease, AIDS-associated dementia, and Down's syndrome; demyelinatingdiseases such as multiple sclerosis and amyotrophic lateral sclerosisand other neuropathological disorders such as peripheral neuropathy,such as diabetic and chemotherapy-induced neuropathy, and post-herpeticand other neuralgias; acute and chronic obstructive airway diseases suchas adult respiratory distress syndrome, bronchopneumonia, bronchospasm,chronic bronchitis, drivercough, and asthma; inflammatory diseases suchas inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis,and rheumatoid arthritis; disorders of the musculo-skeletal system, suchas osteoporosis; allergies such as eczema and rhinitis; hypersensitivitydisorders such as poison ivy; ophthalmic diseases such asconjunctivitis, vernal conjunctivitis, and the like; cutaneous diseasessuch as contact dermatitis, atopic dermatitis, urticaria, and othereczematoid dermatites; addiction disorders such as alcoholism;stress-related somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; dysthymic disorders; adverse immunologicalreactions such as rejection of transplanted tissues and disordersrelated to immune enhancement or suppression such as systemic lupuserythematosis; gastrointestinal disorders or diseases associated withthe neuronal control of viscera such as ulcerative colitis, Crohn'sdisease, emesis, and irritable bowel syndrome; disorders of bladderfunction such as bladder detrusor hyper-reflexia and incontinence;artherosclerosis; fibrosing and collagen diseases such as sclerodermaand eosinophilic fascioliasis; irritative symptoms of benign prostatichypertrophy; disorders of blood flow caused by vasodilation andvasospastic diseases such as angina, migraine, and Raynaud's disease;and pain or nociception, for example, that attributable to or associatedwith any of the foregoing conditions, especially the transmission ofpain in migraine.

NK-1 antagonists are useful in the treatment of pain, especially chronicpain, such as neuropathic pain, post-operative pain, and migraines, painassociated with arthritis, cancer-associated pain, chronic lower backpain, cluster headaches, herpes neuralgia, phantom limb pain, centralpain, dental pain, neuropathic pain, opioid-resistant pain, visceralpain, surgical pain, bone injury pain, pain during labor and delivery,pain resulting from burns, including sunburn, post partum pain, anginapain, and genitourinary tract-related pain including cystitis.

In addition to pain, NK-1 antagonists are especially useful in thetreatment and prevention of urinary incontinence; irritative symptoms ofbenign prostatic hypertrophy; motility disorders of the gastrointestinaltract, such as irritable bowel syndrome; acute and chronic obstructiveairway diseases, such as bronchospasm, bronchopneumonia, asthma, andadult respiratory distress syndrome; artherosclerosis; inflammatoryconditions, such as inflammatory bowel disease, ulcerative colitis,Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenicinflammation, allergies, rhinitis, cough, dermatitis, urticaria,psoriasis, conjunctivitis, emesis, irritation-induced miosis; tissuetransplant rejection; plasma extravasation resulting from cytokinechemotherapy and the like; spinal cord trauma; stroke; cerebral stroke(ischemia); Alzheimer's disease; Parkinson's disease; multiplesclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety; anddepression.

NK-2 antagonists are useful in the treatment of urinary incontinence,bronchospasm, asthma, adult respiratory distress syndrome, motilitydisorders of the gastrointestinal tract, such as irritable bowelsyndrome, and pain.

In addition to the above indications the compounds of the invention maybe useful in the treatment of emesis, including acute, delayed, oranticipatory emesis, such as emesis induced by chemotherapy, radiation,toxins, pregnancy, vestibular disorders, motion, surgery, migraine, andvariations in intercranial pressure. Most especially, the compounds offormula I are of use in the treatment of emesis induced byantineoplastic (cytotoxic) agents including those routinely used incancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, forexample, nitrogen mustards, ethyleneimine compounds, alkyl sulfonates,and other compounds with an alkylating action, such as nitrosoureas,cisplatin, and dacarbazine; antimetabolites, for example, folic acid,purine, or pyrimidine antagonists; mitotic inhibitors, for example vincaalkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.

Particular examples of chemotherapeutic agents are described, forinstance, by D. J. Stewart in NAUSEA AND VOMITING: RECENT RESEARCH ANDCLINICAL ADVANCES, (J. Kucharczyk et al., eds., 1991), at pages 177–203.Commonly used chemotherapeutic agents include cisplatin, dacarbazine(DTIC), dactinomycin, mechlorcthamine (nitrogen mustard), streptozocin,cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin,daunorubicin, procarbazine, mitomycin, cytarabine, etoposide,methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, andchlorambucil. R. J. Gralla et al., Cancer Treatment Reports, 68, 163–172(1984).

The compounds of formula I may also be of use in the treatment of emesisinduced by radiation, including radiation therapy such as in thetreatment of cancer, or radiation sickness; and in the treatment ofpost-operaive nausea and vomiting.

While it is possible to administer a compound employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and at least oneactive ingredient. These compositions can be administered by a varietyof routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Many of the compoundsemployed in the methods of this invention are effective as bothinjectable and oral compositions. Such compositions are prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound. See. e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16thed. 1980).

In making the compositions employed in the present invention the activeingredient is usually mixed with an excipient, diluted by an excipient,or enclosed within such a carrier which can be in the form of a capsule,sachet, paper, or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.05 to about 100 mg, more usually about1.0 to about 30 mg, of the active ingredient. The term “unit dosageform” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compounds are generally effective over a wide dosage range.For examples, dosages per day normally fall within the range of about0.01 to about 30 mg/kg of body weight. In the treatment of adult humans,the range of about 0.1 to about 15 mg/kg/day, in single or divided dose,is especially preferred. However, it will be understood that the amountof the compound actually administered will be determined by a physician,in the light of the relevant circumstances, including the condition tobe treated, the chosen route of administration, the actual compound orcompounds administered, the age, weight, and response of the individualpatient, and the severity of the patient's symptoms, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. In some instances dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smallerdoses for administration throughout the day.

FORMULATION EXAMPLE 1

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Compound of Example 35 30.0 Starch305.0 Magnesium stearate 5.0 The above ingredients are mixed and filledinto hard gelatin capsules in 340 mg quantities.

FORMULATION EXAMPLE 2

A tablet formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Compound of Example 95 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0The components are blended and compressed to form tablets, each weighing240 mg.

FORMULATION EXAMPLE 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Compound of Example 63 5 Lactose 95 The activemixture is mixed with the lactose and the mixture is added to a drypowder inhaling appliance.

FORMULATION EXAMPLE 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Compound of Example 103 30.0 mg Starch45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10%solution in water)  4.0 mg Sodium carboxymethyl starch  4.5 mg Magnesiumstearate  0.5 mg Talc  1.0 mg Total  120 mgThe active ingredient, starch, and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50–60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

FORMULATION EXAMPLE 5

Capsules, each containing 40 mg of medicament are made as follows:

Quantity Ingredient (mg/capsule) Compound of Example 104  40.0 mg Starch109.0 mg Magnesium stearate  1.0 mg Total 150.0 mgThe active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

FORMULATION EXAMPLE 6

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Compound of Example 110   25 mg Saturated fatty acidglycerides to 2,000 mgThe active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7

Suspensions, each containing 50 mg of medicament per 5.0 ml dose aremade as follows:

Ingredient Amount Compound of Example 111 50.0 mg Xanthan gum  4.0 mgSodium carboxymethyl cellulose (11%) 50.0 mg Microcrystalline cellulose(89%) Sucrose 1.75 g  Sodium benzoate 10.0 mg Flavor and Color q.v.Purified water to  5.0 mlThe medicament, sucrose, and xanthan gum are blended, passed through aNo. 10 mesh U.S. sieve, and then mixed with a previously made solutionof the microcrystalline cellulose and sodium carboxymethyl cellulose inwater. The sodium benzoate, flavor, and color are diluted with some ofthe water and added with stirring. Sufficient water is then added toproduce the required volume.

FORMULATION EXAMPLE 8

Capsules, each containing 15 mg of medicament, are made as follows:

Quantity Ingredient (mg/capsule) Compound of Example 112  15.0 mg Starch407.0 mg Magnesium stearate  3.0 mg Total 425.0 mgThe active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 425 mg quantities.

FORMULATION EXAMPLE 9

An intravenous formulation may be prepared as follows:

Ingredient Quantity Compound of Example 120 250.0 mg Isotonic saline 1000 ml

FORMULATION EXAMPLE 10

A topical formulation may be prepared as follows:

Ingredient Quantity Compound of Example 35 1–10 g Emulsifying Wax 30 gLiquid Paraffin 20 g White Soft Paraffin to 100 gThe white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

FORMULATION EXAMPLE 11

Sublingual or buccal tablets, each containing 10 mg of activeingredient, may be prepared as follows:

Quantity Ingredient Per Tablet Compound of Example 95  10.0 mg Glycerol210.5 mg Water 143.0 mg Sodium Citrate  4.5 mg Polyvinyl Alcohol  26.5mg Polyvinylpyrrolidone  15.5 mg Total 410.0 mgThe glycerol, water, sodium citrate, polyvinyl alcohol, andpolyvinylpyrrolidone are admixed together by continuous stirring andmaintaining the temperature at about 90° C. When the polymers have goneinto solution, the resulting solution is cooled to about 50–55° C. andthe medicament is slowly admixed. The homogenous mixture is poured intoforms made of an inert material to produce a drug-containing diffusionmatrix having a thickness of about 2–4 mm. This diffusion matrix is thencut to form individual tablets having the appropriate size.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, which is herein incorporated byreference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonic solutionsthat can transiently open the blood-brain barrier.

The type of formulation employed for the administration of the compoundsemployed in the methods of the present invention may be dictated by theparticular compounds employed, the type of pharmacokinetic profiledesired from the route of administration and the compound(s), and thestate of the patient.

While the invention has been illustrated and described in detail in theforegoing description, such an illustration and description is to beconsidered as exemplary and not restrictive in character, it beingunderstood that only the illustrative embodiments have been shown anddescribed and that all changes and modifications that come within thespirit of the invention are desired to be protected.

1. A compound having the formula

wherein: n is an integer from 0 to 2; A is XNH—, or R⁵XN—; A′ is X′NH—,or R^(5′)X′N—; R² is hydrogen or C₁–C₆ alkyl; R³ is a structure selectedfrom the group consisting of

R⁴ is C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl, C₃–C₉cycloalkenyl, limonenyl, pinenyl, C₁–C₃ alkanoyl, optionally-substitutedaryl, optionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(halo C₁–C₄ alkyl), optionally-substituted aryl(alkoxy C₁–C₄ alkyl),optionally-substituted aryl(C₂–C₄ alkenyl), optionally-substitutedaryl(halo C₂–C₄ alkenyl), or optionally-substituted aryl(C₂–C₄ alkynyl);X is selected from the group consisting of C₁–C₆ alkyl, C₃–C₈cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄ alkyl), optionally-substituted aryl,optionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(C₃–C₇ cycloalkyl), optionally-substituted indan- l-yl,optionally-substituted indan-2-yl, optionally-substituted1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y, Y—(C₁–C₄ alkyl),R⁷R⁸N—, and R⁷R⁸N—(C₂–C₄ alkyl); and R⁵ is selected from the groupconsisting of hydroxy, C₁–C₆ alkyl, C₁–C₄ alkoxycarbonyl, and benzyl; orR⁵ and X are taken together with the attached nitrogen atom to form anoptionally substituted heterocycle selected from the group consisting ofpyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl, where saidheterocycle is optionally substituted with R¹⁰, R¹², R⁷R⁸N—, orR⁷R⁸N—(C₁–C₄ alkyl); X′ is selected from the group consisting of C₁–C₆alkyl, C₃–C₈ cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄ alkyl),optionally-substituted aryl, optionally-substituted aryl(C₁–C₄ alkyl),optionally-substituted aryl(C₃–C₇ cycloalkyl), optionally-substitutedindan-1-yl, optionally-substituted indan-2-yl, optionally-substituted1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y′, Y′—(C₁–C₄ alkyl),R^(7′)R^(8′)N—, and R^(7′)R^(8′)N—(C₂–C₄ alkyl); and R^(5′) is selectedfrom the group consisting of hydroxy, C₁–C₆ alkyl, C₁–C₄ alkoxycarbonyl,and benzyl; or R^(5′) and X′ are taken together with the attachednitrogen atom to form an optionally substituted heterocycle selectedfrom the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, andhomopiperazinyl, where said heterocycle is optionally substituted withR¹⁰, R^(12′), R^(7′)R^(8′)N—, or R^(7′)R^(8′)N—(C₁–C₄ alkyl); where theheterocycle Y and the heterocycle Y′ are each independently selectedfrom the group consisting of tetrahydrofuryl, morpholinyl, pyrrolidinyl,piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; where saidmorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, orquinuclidinyl is optionally N-substituted with C₁–C₄ alkyl oroptionally-substituted aryl(C₁–C₄ alkyl); R⁷ is hydrogen or C₁–C₆ alkyl;and R⁸ is C₁–C₆ alkyl, C₃–C₈ cycloalkyl, optionally-substituted aryl, oroptionally-substituted aryl(C₁–C₄ alkyl); or R⁷ and R⁸ are takentogether with the attached nitrogen atom to form an heterocycle selectedfrom the group consisting of pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, and homopiperazinyl; where said piperazinyl orhomopiperazinyl is optionally N-substituted with R¹²; R^(7′) is hydrogenor C₁–C₆ alkyl; and R^(8′) is C₁–C₆ alkyl, C₃–C₈ cycloalkyl,optionally-substituted aryl, or optionally-substituted aryl(C₁–C₄alkyl); or R^(7′) and R^(8′) are taken together with the attachednitrogen atom to form an heterocycle selected from the group consistingof pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, andhomopiperazinyl; where said piperazinyl or homopiperazinyl is optionallyN-substituted with R^(12′); R¹⁰ and R¹¹ are each independently chosenfrom the group consisting of hydrogen, C₁–C₆ alkyl, C₃–C₈ cycloalkyl,C₁–C₄ alkoxycarbonyl, C₁–C₅ alkanoyloxy, benzyloxy, benzoyloxy,diphenylmethoxy, triphenylmethoxy, optionally-substituted aryl, andoptionally-substituted aryl(C₁–C₄ alkyl); where the C₁–C₆ alkyl or theC₃–C₈ cycloalkyl is optionally monosubstituted with a substituentselected from the group consisting of hydroxy, protected carboxy,carbamoyl, thiobenzyl and C₁–C₄ thioalkyl; and, where the benzyl of saidbenzyloxy or said benzoyloxy is optionally substituted with one or twosubstituents independently selected from the group consisting of C₁–C₄alkyl, C₁–C₄ alkoxy, halogen, hydroxy, cyano, carbamoyl, amino,mono(C₁–C₄ alkyl)amino, di(C₁–C₄ alkyl)amino, C₁–C₄ alkylsulfonylamino,and nitro; R¹² and R^(12′) are each independently selected from thegroup consisting of hydrogen, C₁–C₆ alkyl, C₃–C₈ cycloalkyl, C₁–C₄alkoxycarbonyl, optionally-substituted aryloxycarbonyl,optionally-substituted aryl(C₁–C₄ alkyl), and optionally-substitutedaryloyl; and pharmaceutically acceptable acid addition salts thereof;and providing that when A is XNH— and the integer n is 0, then A′ is notanilinyl, substituted anilinyl, benzylamino, or substituted benzylamino.2. The compound of claim 1, wherein A is XNH—.
 3. The compound of claim1, wherein A is R⁵XN—; where R⁵ is selected from the group consisting ofhydroxy, C₁–C₆ alkyl, C₁–C₄ alkoxycarbonyl, and benzyl; and where X isselected from the group consisting of C₁–C₆ alkyl, C₃–C₈ cycloalkyl,(C₁–C₄ alkoxy)-(C₁–C₄ alkyl), optionally-substituted aryl,optionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(C₃–C₇ cycloalkyl), optionally-substituted indan-1-yl,optionally-substituted indan-2-yl, optionally-substituted1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y, Y—(C₁–C₄ alkyl),R⁷R⁸N—, and R⁷R⁸N—(C₂–C₄ alkyl).
 4. The compound of claim 1, wherein Ais R⁵XN—, where R⁵ and X are taken together with the attached nitrogenatom to form an optionally substituted heterocycle selected from thegroup consisting of pyrrolidinyl, piperidinyl, piperazinyl, andhomopiperazinyl; where said heterocycle is optionally substituted withR¹⁰, R¹², R⁷R⁸N—, or R⁷R⁸N—(C₁–C₄ alkyl).
 5. The compound of claim 4,wherein R⁵ and X are taken together with the attached nitrogen atom toform piperidinyl optionally substituted at the 4-position with hydroxy,C₁–C₆ alkyl, C₃–C₈ cycloalkyl, C₁–C₄ alkoxy, (C₁–C₄ alkoxy)carbonyl,(hydroxy(C₂–C₄ alkyloxy))-(C₂–C₄ alkyl), R⁷R⁸N—, R⁷R⁸N—(C₁–C₄ alkyl),diphenylmethyl, optionally-substituted aryl, optionally-substitutedaryl(C₁–C₄ alkyl), or piperidin-1-yl(C₁–C₄ alkyl).
 6. The compound ofclaim 4, wherein R⁵ and X are taken together with the attached nitrogenatom to form piperazinyl optionally substituted at the 4-position withC₁–C₆ alkyl, C₃–C₈ cycloalkyl, optionally-substituted aryl,optionally-substituted aryl(C₁–C₄ alkyl), α-methylbenzyl, N—(C1–C5alkyl)acetamid-2-yl, N—(C₃–C₈ cycloalkyl)acetamid-2-yl, R⁷R⁸N—, or(C₁–C₄ alkoxy)carbonyl.
 7. The compound of claim 4, wherein R⁵ and X aretaken together with the attached nitrogen atom to form homopiperazinyloptionally substituted in the 4-position with C₁–C₄ alkyl, aryl, oraryl(C₁–C₄ alkyl).
 8. The compound of claim 1, wherein A is R⁵XN—, whereR⁵ and X are taken together with the attached nitrogen atom to form anheterocycle selected from the group consisting of pyrrolidinonyl,piperidinonyl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl,1,2,3,4-tetrahydroisoquinolin-2-yl.
 9. The compound of claim 1, whereinA′ is X′NH—.
 10. The compound of claim 1, wherein A′ is R^(5′)X′N—;where R^(5′) is selected from the group consisting of hydroxy, C₁–C₆alkyl, C₁–C₄ alkoxycarbonyl, and benzyl; and X′ is selected from thegroup consisting of C₁–C₆ alkyl, C₃–C₈ cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄alkyl), optionally-substituted aryl, optionally-substituted aryl(C₁–C₄alkyl), optionally-substituted aryl(C₃–C₇ cycloalkyl),optionally-substituted indan-1-yl, optionally-substituted indan-2-yl,optionally-substituted 1,2,3,4-tetrahydronaphth-1-yl,optionally-substituted 1,2,3,4-tetrahydronaphth-2-yl, the heterocycleY′, Y′—(C₁–C₄ alkyl), R^(7′)R^(8′)N—, and R^(7′)R^(8′)N—(C₂–C₄ alkyl).11. The compound of claim 1, wherein A′ is R^(5′)X′N—, where R^(5′) andX′ are taken together with the attached nitrogen atom to form anoptionally substituted heterocycle selected from the group consisting ofpyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl; where saidheterocycle is optionally substituted with R¹⁰, R^(12′), R^(7′)R^(8′)N—,or R^(7′)R^(8′)N—(C₁–C₄ alkyl).
 12. The compound of claim 11, whereinR^(5′) and X′ are taken together with the attached nitrogen atom to formpiperidinyl optionally substituted at the 4-position with hydroxy, C₁–C₆alkyl, C₃–C₈ cycloalkyl, C₁–C₄ alkoxy, (C₁–C₄ alkoxy)carbonyl,(hydroxy(C₁–C₄ alkyloxy))-(C₁–C₄ alkyl), R^(7′)R^(8′)N—,R^(7′)R^(8′)N—(C₁–C₄ alkyl), diphenylmethyl, optionally-substitutedaryl, optionally-substituted aryl(C₁–C₄ alkyl), or piperidin-1-yl(C₁–C₄alkyl).
 13. The compound of claim 11, wherein R^(5′) and X′ are takentogether with the attached nitrogen atom to form piperazinyl optionallysubstituted at the 4-position with C₁–C₆ alkyl, C₃–C₈ cycloalkyl,optionally-substituted aryl, optionally-substituted aryl(C₁–C₄ alkyl),α-methylbenzyl, N—(C₁–C₅ alkyl)acetamid-2-yl, N—(C₃–C₈cycloalkyl)acetamid-2-yl, R^(7′)R^(8′)N—, or (C₁–C₄ alkoxy)carbonyl. 14.The compound of claim 11, wherein R^(5′) and X′ are taken together withthe attached nitrogen atom to form homopiperazinyl optionallysubstituted in the 4-position with C₁–C₄ alkyl, aryl, or aryl(C₁–C₄alkyl).
 15. The compound of claim 1, wherein A′ is R^(5′)X′N—, whereR^(5′) and X′ are taken together with the attached nitrogen atom to forman heterocycle selected from the group consisting of pyrrolidinonyl,piperidinonyl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl,1,2,3,4-tetrahydroisoquinolin-2-yl.
 16. The compound of claim 2, whereinA′ is X′NH—; where X′ is selected from the group consisting of theheterocycle Y′, Y′—(C₁–C₄ alkyl), R^(7′)R^(8′)N—, andR^(7′)R^(8′)N—(C₂–C₄ alkyl).
 17. The compound of claim 16, wherein X isselected from the group consisting of optionally-substituted aryl(C₁–C₄alkyl), optionally-substituted aryl(C₃–C₇ cycloalkyl), the heterocycleY, Y—(C₁–C₄ alkyl), R⁷R⁸N—, and R⁷R⁸N—(C₂–C₄ alkyl).
 18. The compound ofclaim 2, wherein A′ is R^(5′)XN—, where R^(5′) and X′ are taken togetherwith the attached nitrogen atom to form an heterocycle selected from thegroup consisting of pyrrolidinyl, piperidinyl, piperazinyl, andhomopiperazinyl; where said heterocycle is optionally substituted withR¹⁰, R^(12′), R^(7′)R^(8′)N—, or R^(7′)R^(8′)N—(C₁–C₄ alkyl).
 19. Thecompound of claim 18, wherein X is selected from the group consisting ofoptionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(C₃–C₇ cycloalkyl), the heterocycle Y, Y—(C₁–C₄ alkyl), R⁷R⁸N—, andR⁷R⁸N—(C₂–C₄ alkyl).
 20. The compound of claim 2, wherein A′ is X′NH—,or R^(5′)X′N—; and n is
 1. 21. The compound of claim 2, wherein A′ isX′NH—, or R^(5′)X′N—; and n is
 2. 22. The compound of claim 9, wherein Ais XNH—; where X is selected from the group consisting of theheterocycle Y, Y—(C₁–C₄ alkyl), R⁷R⁸N—, and R⁷R⁸N—(C₂–C₄ alkyl).
 23. Thecompound of claim 22, wherein X′ is selected from the group consistingof optionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(C₃–C₇ cycloalkyl), the heterocycle Y′, Y′—(C₁–C₄ alkyl),R^(7′)R^(8′)N—, and R^(7′)R^(8′)N—(C₂–C₄ alkyl).
 24. The compound ofclaim 9, wherein A is R⁵XN—, where R⁵ and X are taken together with theattached nitrogen atom to form an heterocycle selected from the groupconsisting of pyrrolidinyl, piperidinyl, piperazinyl, andhomopiperazinyl; where said heterocycle is optionally substituted withR¹⁰, R^(12′), R⁷R⁸N—, or R⁷R⁸N—(C₁–C₄ alkyl).
 25. The compound of claim24, wherein X′ is selected from the group consisting ofoptionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(C₃–C₇ cycloalkyl), the heterocycle Y′, Y′—(C₁–C₄ alkyl),R^(7′)R^(8′)N—, and R^(7′)R^(8′)N—(C₂–C₄ alkyl).
 26. The compound ofclaim 9, wherein A is XNH—, or R⁵XN—; and n is
 1. 27. The compound ofclaim 9, wherein A is XNH—, or R⁵XN—; and n is
 2. 28. The compound ofclaim 1, wherein A is R⁵XN—, where R⁵ and X are taken together with theattached nitrogen atom to form an heterocycle selected from the groupconsisting of pyrrolidinyl, piperidinyl, piperazinyl, andhomopiperazinyl; where said heterocycle is optionally substituted withR¹⁰, R¹², R⁷R⁸N—, or R⁷R⁸N—(C₁–C₄ alkyl); and A′ is R^(5′)XN—, whereR^(5′) and X′ are taken together with the attached nitrogen atom to forman heterocycle selected from the group consisting of pyrrolidinyl,pipendinyl, piperazinyl, and homopiperazinyl; where said heterocycle isoptionally substituted with R¹⁰, R^(12′), R^(7′)R^(8′)N—, orR^(7′)R^(8′)N—(C₁–C₄ alkyl) as defined above.
 29. The compound of claim28, wherein n is
 1. 30. The compound of claim 28, wherein n is
 2. 31.The compound of claim 1, wherein R⁴ is optionally-substituted aryl(C₁–C₄alkyl), optionally-substituted aryl(C₂–C₄ alkenyl), oroptionally-substituted aryl(C₂–C₄ alkynyl).
 32. The compound of claim 1,wherein R³ is the structure


33. The compound of claim 1, wherein R² is hydrogen.
 34. The compound ofclaim 1, wherein A is R⁵XN—, where R⁵ and X are taken together with theattached nitrogen atom to form an heterocycle selected from the groupconsisting of pyrrolidinyl, piperidinyl, and piperazinyl; where saidheterocycle is optionally substituted with C₁–C₆ alkyl, C₃–C₈cycloalkyl, R⁷R⁸N—, R⁷R⁸N—(C₁–C₄ alkyl), optionally-substituted aryl, oroptionally-substituted aryl(C₁–C₄ alkyl).
 35. The compound of claim 1,wherein A is XNH—, where X is optionally-substituted aryl(C₁–C₄ alkyl).36. The compound of claim 35, wherein R⁴ is optionally-substitutedaryl(C₁–C₄ alkyl), optionally-substituted aryl(C₂–C₄ alkenyl), oroptionally-substituted aryl(C₂–C₄ alkynyl); R³ is the structure

and R² is hydrogen.
 37. The compound of claim 36, wherein A′ is X′NH—,where X′ is optionally-substituted aryl(C₁–C₄ alkyl), the heterocycleY′, Y′—(C₁–C₄ alkyl), R^(7′)R^(8′)N—, or R^(7′)R^(8′)N—(C₂–C₄ alkyl).38. The compound of claim 37, wherein X′ is R^(7′)R^(8′)N— orR^(7′)R^(8′)N—(C₂–C₄ alkyl).
 39. The compound of claim 37, wherein X′ isthe heterocycle Y′ or Y′—(C₁–C₄ alkyl), where said heterocycle Y′ isselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, and homopiperazinyl, where said heterocycle isoptionally N-substituted with optionally-substituted aryl(C₁–C₄ alkyl).40. The compound of claim 37, wherein the integer n is
 1. 41. Thecompound of claim 37, wherein R^(8′) is selected from the groupconsisting of C₁–C₆ alkyl, C₃–C₈ cycloalkyl, and aryl(C₁–C₄ alkyl). 42.The compound of claim 37, wherein R^(7′) and R^(8′) are taken togetherwith the attached nitrogen atom to form an heterocycle selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,and homopiperazinyl, where said piperazinyl or homopiperazinyl isoptionally substituted at the 4-position with (C₁–C₄ alkyl), (C₃–C₈cycloalkyl), or aryl(C₁–C₄ alkyl).
 43. The compound of claim 36, whereinA′ is R^(5′)X′N—.
 44. The compound of claim 43, wherein R^(5′) isaryl(C₁–C₄ alkyl), and X′ is selected from the group consisting ofoptionally-substituted aryl(C₁–C₄ alkyl), the heterocycle Y′, Y′—(C₁–C₄alkyl), R^(7′)R^(8′)N—, and R^(7′)R^(8′)N—(C₂–C₄ alkyl).
 45. Thecompound of claim 43, wherein R^(8′) is selected from the groupconsisting of C₁–C₆ alkyl, C₃–C₈ cycloalkyl, and aryl(C₁–C₄ alkyl). 46.The compound of claim 43, wherein R^(7′) and R^(8′) are taken togetherwith the attached nitrogen atom to form an heterocycle selected from thegroup consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,and homopiperazinyl, where said piperazinyl or homopiperazinyl isoptionally substituted at the 4-position with (C₁–C₄ alkyl), (C₃–C₈cycloalkyl), or aryl(C₁–C₄ alkyl).
 47. The compound of claim 43, whereinR^(5′) and X′ are taken together with the attached nitrogen atom to forman heterocycle selected from the group consisting of pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, and homopiperazin-1-yl; where saidheterocycle is substituted with C₁–C₆ alkyl, C₃–C₈ cycloalkyl,optionally-substituted aryl, optionally-substituted aryl(C₁–C₄ alkyl),the heterocycle Y′, Y′—(C₁–C₄ alkyl), R^(7′)R^(8′)N—,R^(7′)R^(8′)N—(C₁–C₄ alkyl), or R^(7′)R^(8′)N—C(O)—(C₁–C₄ alkyl). 48.The compound of claim 43, wherein R^(5′) and X′ are taken together withthe attached nitrogen atom to form an heterocycle selected from thegroup consisting of piperidin-1-yl and piperazin-1-yl, where theheterocycle is substituted with C₁–C₆ alkyl, C₃–C₈ cycloalkyl,optionally-substituted aryl(C₁–C₄ alkyl), R^(7′)R^(8′)N—, orR^(7′)R^(8′)N—(C₁–C₄ alkyl).
 49. The compound of claim 48, whereinR^(7′) and R^(8′) are taken together with the attached nitrogen atom toform an heterocycle selected from the group consisting of pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl, where saidpiperazinyl or homopiperazinyl is optionally substituted at the4-position with (C₁–C₄ alkyl), (C₃–C₈ cycloalkyl), or aryl(C₁–C₄ alkyl).50. The compound of claim 43, wherein R^(5′) and X′ are taken togetherwith the attached nitrogen to form piperazin-1-yl, where saidpiperazin-1-yl is substituted with C₁–C₆ alkyl, C₃–C₈ cycloalkyl, oraryl(C₁–C₄ alkyl).
 51. The compound of claim 43, wherein the integer nis
 1. 52. The compound of claim 43, wherein the integer n is
 2. 53. Acompound having the formula

wherein: n′ is an integer from 1 to 3; A is XNH—, or R⁵XN—; R² ishydrogen or C₁–C₆ alkyl; R³ is a structure selected from the groupconsisting of

R⁴ is C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₈ cycloalkyl, C₃–C₉cycloalkenyl, limonenyl, pinenyl, C₁–C₃ alkanoyl, optionally-substitutedaryl, optionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(halo C₁–C₄ alkyl), optionally-substituted aryl(alkoxy C₁–C₄ alkyl),optionally-substituted aryl(C₂–C₄ alkenyl), optionally-substitutedaryl(halo C₂–C₄ alkenyl), or optionally-substituted aryl(C₂–C₄ alkynyl);X is selected from the group consisting of C₁–C₆ alkyl, C₃–C₈cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄ alkyl), optionally-substituted aryl,optionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(C₃–C₇ cycloalkyl), optionally-substituted indan-1-yl,optionally-substituted indan-2-yl, optionally-substituted1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y, Y—(C₁–C₄ alkyl),R⁷R⁸N—, and R⁷R⁸N—(C₂–C₄ alkyl); and R⁵ is selected from the groupconsisting of hydroxy, C₁–C₆ alkyl, C₁–C₄ alkoxycarbonyl, and benzyl;and where X is selected from the group consisting of C₁–C₆ alkyl, C₃–C₈cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄ alkyl), optionally-substituted aryl,optionally-substituted aryl(C₁–C₄ alkyl), optionally-substitutedaryl(C₃–C₇ cycloalkyl), optionally-substituted indan-1-yl,optionally-substituted indan-2-yl, optionally-substituted1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y, Y—(C₁–C₄ alkyl),R⁷R⁸N—, and R⁷R⁸N—(C₂–C₄ alkyl); or R⁵ and X are taken together with theattached nitrogen atom to form an optionally substituted heterocycleselected from the group consisting of pyrrolidinyl, piperidinyl,piperazinyl, and homopiperazinyl, where said heterocycle is optionallysubstituted with R¹⁰, R¹², R⁷R⁸N—, or R⁷R⁸N—(C₁–C₄ alkyl); R^(6′) isselected from the group consisting of C₁–C₆ alkyl, C₃–C₈ cycloalkyl,(C₁–C₄ alkoxy)-(C₁–C₄ alkyl), optionally-substituted aryl(C₁–C₄ alkyl),Y—(C₁–C₄ alkyl), where Y— is an heterocycle, Y′—(C₁–C₄ alkyl), where Y′—is an heterocycle, R⁷R⁸N—(C₂–C₄ alkyl), and R^(7′)R^(8′)N—(C₂–C₄ alkyl);where the heterocycle Y and the heterocycle Y′ are each independentlyselected from the group consisting of tetrahydrofuryl, morpholinyl,pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, orquinuclidinyl; where said morpholinyl, pyrrolidinyl, piperidinyl,piperazinyl, homopiperazinyl, or quinuclidinyl is optionallyN-substituted with C₁–C₄ alkyl or optionally-substituted aryl(C₁–C₄alkyl); R⁷ is hydrogen or C₁–C₆ alkyl; R⁸ is C₁–C₆ alkyl, C₃–C₈cycloalkyl, optionally-substituted aryl, or optionally-substitutedaryl(C₁–C₄ alkyl); or R⁷ and R⁸ are taken together with the attachednitrogen atom to form an heterocycle selected from the group consistingof pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, andhomopiperazinyl; where said piperazinyl or homopiperazinyl is optionallyN-substituted with R¹²; R^(7′) is hydrogen or C₁–C₆ alkyl; R^(8′) isC₁–C₆ alkyl, C₃–C₈ cycloalkyl, optionally-substituted aryl, oroptionally-substituted aryl(C₁–C₄ alkyl); or R^(7′) and R^(8′) are takentogether with the attached nitrogen atom to form an heterocycle selectedfrom the group consisting of pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, and homopiperazinyl; where said piperazinyl orhomopiperazinyl is optionally N-substituted with R^(12′); R¹⁰ and R¹¹are each independently chosen from the group consisting of hydrogen,C₁–C₆ alkyl, C₃–C₈ cycloalkyl, C₁–C₄ alkoxycarbonyl, C₁–C₅ alkanoyloxy,benzyloxy, benzoyloxy, diphenylmethoxy, triphenylmethoxy,optionally-substituted aryl, and optionally-substituted aryl(C₁–C₄alkyl); where the C₁–C₆ alkyl or the C₃–C₈ cycloalkyl is optionallymonosubstituted with a substituent selected from the group consisting ofhydroxy, protected carboxy, carbamoyl, thiobenzyl and C₁–C₄ thioalkyl;and, where the benzyl of said benzyloxy or said benzoyloxy is optionallysubstituted with one or two substituents independently selected from thegroup consisting of C₁–C₄ alkyl, C₁–C₄ alkoxy, halogen, hydroxy, cyano,carbamoyl, amino, mono(C₁–C₄ alkyl)amino, di(C₁–C₄ alkyl)amino, C₁–C₄alkylsulfonylamino, and nitro; R¹² and R^(12′) are each independentlyselected from the group consisting of hydrogen, C₁–C₆ alkyl, C₃–C₈cycloalkyl, C₁–C₄ alkoxycarbonyl, optionally-substitutedaryloxycarbonyl, optionally-substituted aryl(C₁–C₄ alkyl), andoptionally-substituted aryloyl; and pharmaceutically acceptable acidaddition salts thereof.
 54. The compound of claim 53, wherein A is XNH—.55. The compound of claim 53, wherein A is R⁵XN—; where R⁵ is selectedfrom the group consisting of hydroxy, C₁–C₆ alkyl, C₁–C₄ alkoxycarbonyl,and benzyl; and where X is selected from the group consisting of C₁–C₆alkyl, C₃–C₈ cycloalkyl, (C₁–C₄ alkoxy)-(C₁–C₄ alkyl),optionally-substituted aryl, optionally-substituted aryl(C₁–C₄ alkyl),optionally-substituted aryl(C₃–C₇ cycloalkyl), optionally-substitutedindan-1-yl, optionally-substituted indan-2-yl, optionally-substituted1,2,3,4-tetrahydronaphth-1-yl, optionally-substituted1,2,3,4-tetrahydronaphth-2-yl, the heterocycle Y, Y—(C₁–C₄ alkyl),R⁷R⁸N—, and R⁷R⁸N—(C₂–C₄ alkyl).
 56. The compound of claim 53, wherein Ais R⁵XN—, where R⁵ and X are taken together with the attached nitrogenatom to form an heterocycle selected from the group consisting ofpyrrolidinyl, piperidinyl, piperazinyl, and homopiperazinyl; where saidheterocycle is optionally substituted with R₁₀, R¹², R⁷R⁸N—, orR⁷R⁸N—(C₁–C₄ alkyl).
 57. The compound of claim 56, wherein R⁵ and X aretaken together with the attached nitrogen atom to form piperidinyloptionally substituted at the 4-position with hydroxy, C₁–C₆ alkyl,C₃–C₈ cycloalkyl, C₁–C₄ alkoxy, (C₁–C₄ alkoxy)carbonyl, (hydroxy(C₂–C₄alkyloxy))-(C₂–C₄ alkyl), R⁷R⁸N—, R⁷R⁸N—(C₁–C₄ alkyl), diphenylmethyl,optionally-substituted aryl, optionally-substituted aryl(C₁–C₄ alkyl),or piperidin-1-yl(C₁–C₄ alkyl).
 58. The compound of claim 56, wherein R⁵and X are taken together with the attached nitrogen atom to formpiperazinyl optionally substituted at the 4-position with C₁–C₆ alkyl,C₃–C₈ cycloalkyl, optionally-substituted aryl, optionally-substitutedaryl(C₁–C₄ alkyl), α-methylbenzyl, N—(C1–C5 alkyl)acetamid-2-yl,N—(C₃–C₈ cycloalkyl)acetamid-2-yl, R⁷R⁸N—, or (C₁–C₄ alkoxy)carbonyl.59. The compound of claim 56, wherein R⁵ and X are taken together withthe attached nitrogen atom to form homopiperazinyl optionallysubstituted in the 4-position with C₁–C₄ alkyl, aryl, or aryl(C₁–C₄alkyl).
 60. The compound of claim 53, wherein A is R⁵XN—, where R⁵ and Xare taken together with the attached nitrogen atom to form anheterocycle selected from the group consisting of pyrrolidinonyl,piperidinonyl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl,1,2,3,4-tetrahydroisoquinolin-2-yl.
 61. The compound of claim 53,wherein R⁴ is optionally-substituted aryl(C₁–C₄ alkyl),optionally-substituted aryl(C₂–C₄ alkenyl), or optionally-substitutedaryl(C₂–C₄ alkynyl).
 62. The compound of claim 53, wherein R³ is thestructure


63. The compound of claim 53, wherein R² is hydrogen.
 64. The compoundof claim 53, wherein A is R⁵XN—, where R⁵ and X are taken together withthe attached nitrogen atom to form an heterocycle selected from thegroup consisting of pyrrolidinyl, piperidinyl, and piperazinyl; wheresaid heterocycle is optionally substituted with C₁–C₆ alkyl, C₃–C₈cycloalkyl, R⁷R⁸N—, R⁷R⁸N—(C₁–C₄ alkyl), optionally-substituted aryl, oroptionally-substituted aryl(C₁–C₄ alkyl).
 65. The compound of claim 53,wherein A is XNH—, where X is optionally-substituted aryl(C₁–C₄ alkyl).66. The compound of claim 65, wherein R⁴ is optionally-substitutedaryl(C₁–C₄ alkyl), optionally-substituted aryl(C₂–C₄ alkenyl), oroptionally-substituted aryl(C₂–C₄ alkynyl); R³ is the structure

and R² is hydrogen.
 67. The compound of claim 53, wherein the integer n′is
 1. 68. The compound of claim 53, wherein the integer n′ is
 2. 69. Apharmaceutical formulation comprising a compound of claim 1, and apharmaceutically acceptable carrier, diluent, or excipient therefor. 70.A pharmaceutical formulation comprising a compound of claim 53, and apharmaceutically acceptable carrier, diluent, or excipient therefor.